Extended release compositions comprising trihexyphenidyl

ABSTRACT

The present disclosure provides extended release trihexyphenidyl compositions suitable for once- or twice-daily administration. The compositions comprise a core comprising at least one organic acid; at least one drug layer comprising trihexyphenidyl or a pharmaceutically acceptable salt thereof over the core; and a functional coat over the drug-layered core. The compositions of the disclosure provide extended release with reduced Cmax, a Cmin:Cmax ratio of ≥0.4, Fluctuation Index of ≤1, while providing and maintaining at least a minimum therapeutically effective plasma concentration, of the trihexyphenidyl or the pharmaceutically acceptable salt thereof for at least about 10 hours. The compositions of the disclosure improve solubility of the trihexyphenidyl or the pharmaceutically acceptable salt thereof at a pH of greater than or equal to 5, to provide and maintain at least a minimum effective concentration of the drug at such pH.

1. RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/166,266, filed Feb. 3, 2021.

2. TECHNICAL FIELD

The present disclosure provides extended release (ER) trihexyphenidyl(THP) compositions suitable for once or twice daily administration. Thecompositions provide an acid microenvironment that improves thesolubility of trihexyphenidyl (THP) at a pH greater than or equal toabout 5 and helps to provide and maintain therapeutic plasmaconcentrations of THP for at least about 10 hours, under physiologicallyrelevant conditions. The compositions of the disclosure provide extendedrelease PK profile with reduced dose related peak-to-troughfluctuations, e.g., providing C_(min):C_(max) ratio of greater than orequal to 0.4 and Fluctuation Index (FI) of less than or equal to 1, forimproved tolerability and reduced adverse effects associated with highplasma concentrations and high peak-to-trough fluctuations. The ERtrihexyphenidyl compositions of the disclosure include pellets suitablefor dosing in capsules, sachets, administration with feeding tube, andas sprinkles on food.

3. BACKGROUND

Dystonia is a central nervous system (CNS) disorder associated withoveractivity of cholinergic interneurons (ChIs) that provideacetylcholine (Ach) to medium spiny neurons (MSNs). Overactivity ofcholinergic interneurons produces more acetylcholine for uptake bymedium spiny neurons leading to dystonia. Trihexyphenidyl, a phenylpropylamine (also known as benzhexol and trihex) is an anticholinergicagent that binds to medium spiny neurons and prevents uptake ofacetylcholine by the medium spiny neurons. THP is a syntheticantispasmodic drug that is widely used in the treatment of patients withall forms of parkinsonism, including primary or idiopathic Parkinson'sdisease, secondary symptomatic parkinsonism (postencephalitic,arteriosclerotic, infection-induced, tumor-induced, trauma-induced, anddrug-induced), and involuntary movements due to side effects of certainpsychiatric drugs. Cheung et al. (1988) “Pharmacokinetic evaluation of asustained release formulation of trihexyphenidyl in healthy volunteers”J. Pharm. Sci., 77(9):748-50. It is approved by the FDA as an adjunct inthe treatment of all forms of parkinsonism and for the control ofextrapyramidal disorders caused by central nervous system drugs such asdibenzoxazepines, phenothiazines, thioxanthenes, and butyrophenones. THPis also used off-label for treating primary dystonia, dystoniaassociated with cerebral palsy (dyskinetic cerebral palsy), and/orsialorrhea.

THP, chemically known as α-cyclohexyl-α-phenyl-1-piperidinepropanol, hasthe following chemical structure:

Trihexyphenidyl hydrochloride (THP HCl) was introduced as a syntheticdrug for treatment of Parkinson's disease in 1949. Dosahay and Schwab(1962) “Slow-release Trihexyphenidyl in Parkinson's Disease” JAMA,180(2):159-61. It has proved to be one of the more useful drugs for thetreatment of Parkinson's disease and has been available in 2 mg and 5 mgscored tablets for many years. Corbin (1949) “Trihexyphenidyl:Evaluation of New Agent in Treatment of Parkinsonism” JAMA,141(6):377-82.

The two major problems associated with THP are its poor tolerability andthe need for frequent administration. In addition, some patients withdystonia are on feeding tubes that require the treatment to beadministered via feeding tubes (Dys-Society-2020). THP has the potentialto cause clinically important and dose limiting anti-cholinergic adverseeffects (AEs), such as drowsiness, confusion, dizziness, constipation,urinary retention, and blurred vision (NDA #006773, 2003). Due to poortolerability, the treatment is initiated at a very low dose and titratedslowly over several weeks until the optimum dose is achieved. Also, tomanage the side effects, THP is generally administered in divided doses,typically three-times-a day. If the side effects become intolerable, thedose is reduced, or the drug is stopped. Further, THP hydrochloride, dueto its poor solubility at pH greater than or equal to about 5, exhibitshighly variable plasma levels after oral administration as extendedrelease dosage forms.

The approved and currently marketed IR THP hydrochloride products haveside effects, e.g., drowsiness, dizziness or blurred vision, dry mouth,stomach upset, vomiting, diarrhea, constipation, and difficulty inurinating, associated with high peak serum concentrations (C_(max)) andhigh peak-to-trough fluctuations comprising trough-to-peak concentrationratios (C_(min):C_(max)) of less than about 0.4 and FI of greaterthan 1. In elderly individuals, if the dosage strength is too high, theside effects are urinary difficulty and/or retention, confusion,agitation, and hallucinations, particularly during the night. Dosahayand Schwab, supra. Such adverse effects that can be reducedapproximately by 50% with the use of controlled release formulations(Cheung, 1988).

Additionally, unlike other compounds employed in the treatment ofParkinson's disease, THP shows little tendency towards an increase intolerance and can be used with consistent benefit for over ten years.Further, THP is an efficient drug that is safe and has a long period ofclinical experience. The above-mentioned advantages of THP make it anideal candidate for extended release formulations that can provide andmaintain reasonably stable therapeutically effective plasmaconcentrations.

However, dosing at higher strengths as ER dosage forms results invarious side effects associated with an initial drug release in anamount that is higher than the therapeutic range (e.g., a burst releaseof the drug) and highly variable blood plasma levels after oraladministration due to poor solubility of THP at a pH greater than orequal to about 5, e.g., decrease in solubility of THP as the dosage formpasses through the intestine. Thus, it is desirable to develop ER THPcompositions that can reduce variations in plasma concentrations of thedrug, associated with a reduction in solubility at a pH of greater thanabout 5 in the lower GI tract, e.g., intestine, and reduce side effectsassociated with presently approved IR compositions.

There is currently no extended release product in the market. There is aneed for extended release THP formulation that can improve patientcompliance and tolerability by reducing the C_(max) andC_(max)-to-C_(min) fluctuations (FI) and increasing the C_(min):C_(max)ratio to greater than or equal to 0.4, while providing therapeuticplasma concentrations throughout the day with once-daily dosing.

There is a need to develop once-a-day extended release THP compositions,which can provide at least a 10-hour, preferably from about 16-hour toabut 24-hour, release profile of trihexyphenidyl hydrochloride underphysiologically relevant conditions, improve drug solubility at pH ofgreater than or equal to about 5, reduce side effects associated withunwanted initial burst in drug release, enable sprinkling on food orliquid, enable administration with feeding tube, and exhibit shelf lifeof 2 years at controlled room temperature conditions.

In certain embodiments, the present disclosure provides for apharmaceutical pellet composition comprising a core comprising at leastone organic acid; a first drug layer covering at least a portion of thecore; and a functional coat covering at least a portion of the firstdrug layer. The first drug layer comprises trihexyphenidyl or apharmaceutically acceptable salt thereof, and a nonionic water-solublepolymer. The functional coat comprises a nonionic water-insolublepolymer, and a pore former in a weight ratio of from about 50:50 toabout 98:2. The functional coat has a coating weight gain of from about5% w/w to about 40% w/w, based on the total weight of the compositionwithout the functional coat. The trihexyphenidyl or the pharmaceuticallyacceptable salt thereof, and the organic acid are present in a weightratio of from about 1:5 to about 1:100. The organic acid improvessolubility of the trihexyphenidyl or the pharmaceutically acceptablesalt thereof, in the portions of the GI tract with pH of greater than orequal to 5, to provide and maintain at least a minimum therapeuticplasma concentration of the trihexyphenidyl or the pharmaceuticallyacceptable salt thereof at such pH. The composition provides extendedrelease of trihexyphenidyl, or the pharmaceutically acceptable saltthereof, with a Fluctuation Index (FI) of ≤1.

In certain embodiments, the core is a pellet, bead, seed, or a granulecomprising at least one organic acid. In certain embodiments, the coreis a pellet, bead, seed, or a granule coated with at least one coatingcomprising at least one organic acid. In certain embodiments, the coreis an organic acid or a mixture of organic acids.

In certain embodiments, the first drug layer comprises trihexyphenidylhydrochloride.

In certain embodiments, the organic acid is selected from the groupconsisting of tartaric acid, citric acid, fumaric acid, succinic acid,malic acid, and mixtures thereof.

In certain embodiments, the nonionic water-soluble polymer in the druglayer is selected from the group consisting of hydroxypropyl cellulose,methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose,polyethylene glycol, polyvinyl alcohol, poloxamer, polyvinylpyrrolidone-vinyl acetate copolymer (e.g., copovidone), and mixturesthereof.

In certain embodiments, the nonionic water-insoluble polymer in thefunctional coat is selected from the group consisting of ethylcellulose, cellulose acetate, cellulose diacetate, cellulose triacetate,cellulose propionate, a polyvinyl acetate dispersion, and mixturesthereof.

In certain embodiments, the pore former is an enteric polymer selectedfrom the group consisting of cellulose acetate phthalate, celluloseacetate succinate, methylcellulose phthalate, hydroxyethyl cellulosephthalate, polyvinyl acetate phthalate, polyvinyl butyrate acetate,vinyl acetate-maleic anhydride copolymer, methacrylic acid copolymer,hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate,cellulose acetyl phthalate, and mixtures thereof.

In certain other embodiments, the pore former is a nonionic,pH-independent water-soluble polymer selected from the group consistingof methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, polyethylene glycol, polyvinylalcohol, poloxamer, polyvinyl pyrrolidone-vinyl acetate copolymer (e.g.,copovidone), and mixtures thereof.

In certain embodiments, the first drug layer further comprises at leastone organic acid selected from the group consisting of tartaric acid,citric acid, fumaric acid, succinic acid, malic acid, and mixturesthereof.

In certain embodiments, the composition further comprises a second druglayer, covering at least a portion of the functional coat, andcomprising trihexyphenidyl or a pharmaceutically acceptable saltthereof.

In certain embodiments, the composition provides and maintains at leasta minimum therapeutic plasma concentration of the trihexyphenidyl or thepharmaceutically acceptable salt thereof for at least about 10 hours.

In certain embodiments, the composition is suitable for once-a-dayadministration. In certain embodiments, the present disclosure providesfor a pharmaceutical composition comprising a core comprising at leastone organic acid; a first drug layer covering at least a portion of thecore; and a functional coat covering at least a portion of the firstdrug layer. The first drug layer comprises trihexyphenidyl or apharmaceutically acceptable salt thereof, and a nonionic water-solublepolymer. The functional coat comprises a nonionic water-insolublepolymer, and a pore former in a weight ratio of from about 50:50 toabout 98:2. The functional coat has a coating weight gain of from about5% w/w to about 40% w/w, based on the total weight of the compositionwithout the functional coat. The trihexyphenidyl or the pharmaceuticallyacceptable salt thereof, and the organic acid are present in a weightratio of from about 1:5 to about 1:100. The organic acid improvessolubility of the trihexyphenidyl or the pharmaceutically acceptablesalt thereof, in the portions of the GI tract with pH of greater than orequal to 5, to provide and maintain at least a minimum therapeuticplasma concentration of trihexyphenidyl or the pharmaceuticallyacceptable salt thereof at such pH. The composition provides extendedrelease of the trihexyphenidyl or the pharmaceutically acceptable saltthereof, with a C_(min):C_(max) ratio of ≥0.4.

In certain embodiments, the core is a pellet, bead, seed, or a granulecomprising at least one organic acid. In certain embodiments, the coreis a pellet, bead, seed, or a granule coated with at least one coatingcomprising at least one organic acid. In certain embodiments, the coreis an organic acid or a mixture of organic acids.

In certain embodiments, the disclosure provides a method for making apharmaceutical pellet composition comprising trihexyphenidyl or apharmaceutically acceptable salt thereof, the method comprising:

a) coating a core comprising at least one organic acid with a first druglayer comprising trihexyphenidyl or a pharmaceutically acceptable saltthereof, and a nonionic water-soluble polymer to obtain a drug layeredcore, and

b) coating the drug layered core with a functional coat comprising anonionic water-insoluble polymer, and a pore former.

The nonionic water-insoluble polymer and the pore former are present ina weight ratio of from about 50:50 to about 98:2; the trihexyphenidyl orthe pharmaceutically acceptable salt thereof, and the organic acid arepresent in a weight ratio of from about 1:5 to about 1:100; and thefunctional coat has a coating weight gain of from about 5% to about 40%w/w, based on the total weight of the pellet without the functionalcoat. The organic acid improves solubility of the trihexyphenidyl or thepharmaceutically acceptable salt thereof, in the portions of the GItract with pH of greater than or equal to 5, to provide and maintain atleast a minimum therapeutic plasma concentration of trihexyphenidyl orthe pharmaceutically acceptable salt thereof at such pH. The compositionprovides extended release of the trihexyphenidyl or the pharmaceuticallyacceptable salt thereof, with a C_(min):C_(max) ratio of ≥0.4.

In certain embodiments, the core is an organic acid or a mixture oforganic acids; comprises at least one organic acid; or is a pellet,bead, seed, or a granule coated with at least one coating comprising atleast one organic acid.

In certain embodiments, the disclosure provides a method for treatingdystonia, sialorrhea, and/or dyskinesia. The method comprises orallyadministering to a subject in need thereof, a pharmaceutical compositioncomprising a core comprising at least one organic acid; a first druglayer covering at least a portion of the core; and a functional coatcovering at least a portion of the first drug layer. The first druglayer comprises trihexyphenidyl or a pharmaceutically acceptable saltthereof, and a nonionic water-soluble polymer. The functional coatcomprises a nonionic water-insoluble polymer and a pore former in aweight ratio of from about 50:50 to about 98:2. The functional coat hasa coating weight gain of from about 5% w/w to about 40% w/w, based onthe total weight of the composition without the functional coat. Thetrihexyphenidyl or the pharmaceutically acceptable salt thereof, and theorganic acid are present in a weight ratio of from about 1:5 to about1:100. The organic acid improves solubility of the trihexyphenidyl orthe pharmaceutically acceptable salt thereof, in the portions of the GItract with pH of greater than or equal to 5, to provide and maintain atleast a minimum therapeutic plasma concentration of the trihexyphenidylor the pharmaceutically acceptable salt thereof at such pH. Thecomposition provides extended release of trihexyphenidyl or thepharmaceutically acceptable salt thereof, with a C_(min):C_(max) ratioof ≥0.4.

5. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 compares kinetic solubility of THP HCl (API control (Ctrl)) andTHP HCl-tartaric acid pellets at different drug:tartaric acid weightratios (as represented by 25%, 50%, 75%, and 100% of drug layering),performed using USP Apparatus I at 100 RPM and 37° C., in 900 ml of pH6.8 phosphate buffer. FIG. 1 demonstrates that presence of tartaricacid-containing cores increased the amount of THP released at a pH ofabout 6.8. The figure further demonstrates that increasing the amount ofdrug layer reduced the amount of THP released at a pH of about 6.8.

FIG. 2 compares two-stage dissolution profiles of THP HCl pellets withand without a functional coat, Pellet 1 coated with a functional coat;and Pellet 1 without a functional coat, performed using USP Apparatus Iat 100 RPM and 37° C., in 900 ml of 0.01 N HCl for 1 hour followed bydissolution in 900 ml of pH 6.8 phosphate buffer for 24 hours, tosimulate physiological conditions. FIG. 2 demonstrates that Pellet 1without a functional coat provided faster dissolution/higher dissolutionrate compared to the Pellet 1 with a functional coat.

FIG. 3 compares two-stage dissolution profiles of Pellet 1 (containingtartaric acid:THP HCl weight ratio of about 10:1) and Pellet 2(containing tartaric acid:THP HCl weight ratio of about 40:1), performedusing USP Apparatus I at 100 RPM and 37° C., in 900 ml of 0.01 N HCl for1 hour followed by dissolution in 900 ml of pH 6.8 phosphate buffer for24 hours, to simulate physiological conditions. FIG. 3 demonstrates thatPellet 2 containing tartaric acid:THP HCl weight ratio of 40:1, providedfaster dissolution with an initial burst release of THP compared toPellet 1 containing tartaric acid:THP HCl weight ratio of about 10:1.

FIG. 4 compares dissolution profiles of Pellet 1 formulation andmarketed IR THP HCl tablets (5 mg), performed using USP Apparatus I at100 RPM and 37° C., in 900 ml of pH 6.8 phosphate buffer for 24 hours.FIG. 4 demonstrates that the marketed IR THP HCl tablets provided higherdissolution rate with an initial burst release of THP HCl compared toPellet 1 formulation. FIG. 4 demonstrates that the IR marketed productprovided rapid and uncontrolled initial burst release of THP compared toPellet 1.

FIG. 5 compares two-stage dissolution profiles of THP HCl Pellet 7 with20% functional coating weight gain, based on the total weight of Pellet7 without the functional coat, and Pellet 8 with 25% functional coatingweight gain, based on the total weight of Pellet 8 without thefunctional coat, performed using USP Apparatus I at 100 RPM and 37° C.,in 900 ml of 0.01 N HCl for 1 hour followed by dissolution in 900 ml ofpH 6.8 phosphate buffer for 24 hours, to simulate physiologicalconditions. FIG. 5 demonstrates that release of THP HCl reduced withincrease in functional coating weight gain.

FIG. 6 compares two-stage dissolution profiles for trihexyphenidylhydrochloride Pellets 5, 11, 12, and 13 containing 25%, 20%, 30%, and35% coating weight gain in the functional coat, respectively, based onthe total weight of the corresponding uncoated pellet, performed usingUSP Apparatus I at 100 RPM and 37° C., in 900 ml of pH 1.2 HCl for 1hour followed by dissolution in 900 ml of pH 6.8 phosphate buffer for 24hours, to simulate physiological conditions. FIG. 6 demonstrates thatthe release rate increased with decreasing functional coat weight gain.Pellets with 20% functional coat weight gain provided a maximum releaserate and recovery of THP HCl, and pellets with 35% functional coatweight provided lowest release rate and recovery of THP HCl.

FIG. 7 compares two-stage dissolution profiles of trihexyphenidylhydrochloride Pellets 5, 15, and 16, performed using USP Apparatus I at100 RPM and 37° C., in 900 ml of pH 1.2 HCl for 1 hour followed bydissolution in 900 ml of pH 6.8 phosphate buffer for 24 hours, tosimulate physiological conditions. FIG. 7 demonstrates that Pellet 5(without IR drug layer-2) provided a lag time of about 2 hours, andPellets 15 and 16 (containing IR drug layer-2) did not exhibit any lagtime. FIG. 7 further demonstrates that Pellets 15 and 16 provided higherdrug recovery compared to Pellet 5 (without an IR drug layer).

FIG. 8 compares pharmacokinetic data for Artane IR (5 mg BID), andArtane ER (10 mg QD) (see, Cheung et al. (1988), supra) with a 5 mgextended release composition of the disclosure (Test T) (normalized at10 mg). FIG. 8 demonstrates that Test T provided sustained release ofTHP over an extended time period compared to Artane IR (5 mg BID) andArtane ER (10 mg QD).

FIG. 9 compares a two-stage dissolution profile of Pellets 3, 4, and 6,performed using USP Apparatus I at 100 RPM and 37° C., in 900 ml of pH1.2 HCl for 1 hour followed by dissolution in 900 ml of pH 6.8 phosphatebuffer for 24 hours. FIG. 9 demonstrates that Pellet 3, containing ethylcellulose and hypromellose phthalate (HP 55), provided better controlledrelease of the drug compared to Pellet 4, containing ethyl cellulose andhypromellose (Methocel E5 Prem LV), and Pellet 6 containing EudragitS100 and hypromellose phthalate (HP 55) in the functional coat.

FIG. 10 compares PK performance of extended release THP HCl capsulescontaining Pellet 8 (5 mg, QD dosing) of the present disclosure with amarketed immediate release THP HCl product (5 mg, QD dosing). The figuredemonstrates that the extended release THP capsules provided reducedinitial burst release, while providing therapeutic concentrations of THPHCl over at least about 16 hours, compared to marketed immediate releaseTHP tablets. C_(max) of the extended release capsules containing Pellet8 was about 25% of the marketed immediate release product.

FIG. 11 compares PK performance of extended release THP HCl capsulescontaining Pellet 17 (pellet weight adjusted to 6 mg strength) of thepresent disclosure, administered once-a-day, with marketed immediaterelease THP HCl product (2 mg), administered 3 times-a-day. The figuredemonstrates that the extended release THP capsules, administeredonce-a-day, provided substantially reduced C_(max)-to-C_(min)fluctuations (e.g., C_(min):C_(max) ratio of ≥0.4) compared to marketedimmediate release 2 mg THP tablets administered three-times-a-day, whileproviding therapeutic concentrations of THP HCl over about 24 hours,

FIG. 12 compares pharmacokinetic data from a single dose PK studyconducted in healthy volunteers, under fed conditions, for extendedrelease THP HCl capsules containing functional coated Pellet 14 withoutIR drug layer (e.g., Pellet 14 without Seal Coat-2 and Drug Layer 2),and extended release THP HCl capsules containing Pellet 8. The extendedrelease capsules used in the two PK studies contained THP HCl at a fillweight of ˜5 mg, wherein the entire THP HCl was present in the extendedrelease Drug Layer 1. FIG. 12 demonstrates that at a given strength, thecompositions of the disclosure exhibit minimal inter-study variabilityin plasma concentration of THP over an extended time period, e.g., thePK profile of the composition is reproducible at a given strength.

FIG. 13 compares pharmacokinetic data from a single dose pharmacokinetic(PK) study conducted in healthy volunteers, under fed and fastingconditions, for extended release THP capsules containing pellet 25 (6 mgTHP HCl) of the present disclosure with a Reference Product (R)/marketedimmediate release THP HCl tablet (2 mg THP). FIG. 13 demonstrates thatthe extended release THP capsules, QD dosing, in both fed and fastedconditions, provided substantially reduced C_(max)-to-C_(min)fluctuations (e.g., C_(min):C_(max) ratio of ≥0.4 and FI of ≤1), whileproviding therapeutic concentrations of THP HCl over about 24 hours,compared to marketed immediate release 2 mg THP tablets, QD dosing.

FIG. 14 compares pharmacokinetic data from a single dose pharmacokinetic(PK) study conducted in healthy volunteers, under fed conditions, forextended release THP HCl capsules containing Pellet 25 (6 mg THP HClwithout Drug layer-2)), with capsules containing modified Pellet 14,(e.g., Pellet 14 without Seal Coat-2 and Drug Layer 2) and dosenormalized to 6 mg. The extended release capsules used in the two PKstudies contained THP HCl in the extended release Drug Layer 1. FIG. 14demonstrates that at a given strength, the compositions of thedisclosure exhibit minimal inter-study variability in plasmaconcentration of THP over an extended time period, e.g., the PK profileof the composition is reproducible at a given strength.

FIG. 15 compares PK data for extended release capsules containing Pellet25 (6 mg THP HCl) and of reference product R (QD dose simulated forTID), in normal healthy adult human subjects under fed conditions. Thedata from FIG. 15 demonstrates that under fed conditions, the extendedrelease THP capsules (6 mg), administered once-a-day, providedsubstantially reduced C_(max)-to-C_(min) fluctuations(e.g.,C_(min):C_(max) ratio of ≥0.4 and FI of ≤1), while providing therapeuticplasma concentrations of THP HCl over about 24 hours, compared tomarketed immediate release 2 mg THP tablets administeredthree-times-a-day.

FIG. 16 compares PK data for extended release capsules containing Pellet25 (6 mg THP) and of reference product R (QD dosed simulated for TID),in normal healthy adult human subjects under fasting conditions. Thedata from FIG. 16 demonstrates that under fasting conditions, theextended release THP capsules (6 mg), administered once-a-day, providedsubstantially reduced C_(max)-to-C_(min) fluctuations (e.g.,C_(min):C_(max) ratio of ≥0.4 and FI of ≤1), while providing therapeuticplasma concentrations of THP HCl over about 24 hours, compared tomarketed immediate release 2 mg THP tablets administeredthree-times-a-day.

6. DETAILED DESCRIPTION

The presently disclosed subject matter provides ER trihexyphenidyl(e.g., THP HCl) compositions suitable for once- or twice-dailyadministration. The ER THP compositions of the disclosure reduce drugtoxicity and drug-related side effects, compared to IR THP compositions,by reducing C_(max), providing C_(min):C_(max) ratio of ≥0.4 and FI of≤1, and providing consistent plasma levels of the drug by improving drugsolubility at pH of greater than or equal to about 5.

The compositions of the disclosure provide membrane-controlled extendedrelease of THP or a pharmaceutically acceptable salt thereof, whereinthe membrane controls the drug release in the stomach and extends therelease of the drug in lower regions of the gastrointestinal (GI) tract,wherein the pH is greater than or equal to about 5. The compositions ofthe disclosure provide an acid microenvironment within the dosage formto improve the solubility of THP or a pharmaceutically acceptable saltthereof, as the dosage form passes through the portions of the GI tractwith a pH greater than or equal to about 5. The membrane-controlledextended release and the presence of an acid microenvironment within thedosage form to improve drug solubility, helps the dosage form to provideand maintain at least a minimum therapeutic plasma concentration of THPor a pharmaceutically acceptable salt thereof, while providing Cmin:Cmaxratio of ≥0.4 and FI of ≤1. The ER THP compositions of the disclosureinclude pellets suitable for dosing in capsules, sachets, sprinkling onfood or liquid, and administration via feeding tube. In certainembodiments, the extended release compositions of the disclosure, withor without an immediate release drug layer (e.g., drug layer-2), areformulated to reduce fluctuations in plasma levels of trihexyphenidylthroughout the day (24-hour period), as compared to ARTANE® (2 mg TID)or ARTANE® (5 mg BID). In certain embodiments, the extended releasedosage forms of the disclosure, with or without an immediate releasedrug layer, are formulated to reduce dose related peak-to-troughfluctuations (Fluctuation Index) in plasma levels of trihexyphenidyl. Incertain embodiments, a decrease in Fluctuation Index indicates adecrease in drug plasma fluctuation between the peak-to-trough plasmalevels (e.g., Cmax:Cmin ratio) of trihexyphenidyl; and an increase inFluctuation Index indicates an increase in drug plasma fluctuationbetween the peak-to-trough plasma levels (e.g., Cmax:Cmin ratio) oftrihexyphenidyl. A Fluctuation Index of zero indicates no fluctuationsin drug plasma levels, e.g., as observed in intra venous infusion atsteady state. In certain embodiments, the extended releasetrihexyphenidyl compositions of the disclosure, upon a single doseadministration, provide a Fluctuation Index of ≤1, e.g., from about 0.1to about 1. In certain embodiments, the extended release trihexyphenidylcompositions of the disclosure provide a Fluctuation Index(Cmax−Cmin/Cav) of about 0.1, about 0.2, about 0.3, about 0.4, about0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, or anyintermediate values therein. In certain embodiments, the compositions ofthe disclosure provide extended release of THP, or a pharmaceuticallyacceptable salt thereof, for at least about 10 hours, e.g., from about16 hours to about 24 hours, and exhibit a shelf life of at least about 2years at controlled room temperature conditions.

In certain embodiments, the disclosure provides methods for making ERpellets of THP or a pharmaceutically acceptable salt thereof. In certainembodiments, the disclosure provides methods for making trihexyphenidylcapsules containing extended release THP pellets. In certainembodiments, the disclosure provides methods for improving patientcompliance by administering to the patient an extended release THPcomposition that can provide extended release PK profile with reduceddose related peak-to-trough fluctuations, e.g., providingC_(min):C_(max) ratio of greater than or equal to 0.4 and/or FluctuationIndex of ≤1, for improved tolerability and reduced adverse effectsassociated with high plasma concentrations and high peak-to-troughfluctuations. In certain embodiments, the disclosure provides methodsfor improving patient compliance by administering to the patient anextended release THP composition that can be administered as pellets fordosing in capsules, sachets, administration with feeding tube, and assprinkles on food. In certain embodiments, the disclosure providesmethods of treating all forms of parkinsonism, e.g., postencephalitic,arteriosclerotic, and idiopathic parkinsonism, using extended releaseTHP compositions of the disclosure. In certain embodiments,trihexyphenidyl hydrochloride compositions of the disclosure are used asadjuvant therapy with levodopa when treating the above-mentioned formsof parkinsonism. In certain embodiments, the disclosure provides methodsfor treating primary dystonia, dystonia associated with cerebral palsy(dyskinetic cerebral palsy), and/or sialorrhea, using extended releaseTHP compositions of the disclosure. In certain embodiments, the THPcompositions of the disclosure are used for controlling extrapyramidaldisorders caused by central nervous system drugs such asdibenzoxazepines, phenothiazines, thioxanthenes, and butyrophenones.

For clarity and not by way of limitation, this detailed description isdivided into the following subportions:

-   -   5.1. Definitions;    -   5.2. Formulations of Pellet Dosage Forms;    -   5.3. Compositions;    -   5.4. Methods of Making; and    -   5.5. Methods of Use.

6.1. Definitions

The terminology used in the present disclosure is for the purpose ofdescribing particular embodiments only and is not intended to belimiting. Certain terms are discussed below, or elsewhere in thespecification, to provide additional guidance in describing thecompositions and methods of the disclosure and how to make and use them.Unless otherwise defined, all terms, including technical and scientificterms used in the description, have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this disclosurebelongs.

As used herein, the use of the word “a” or “an” when used in conjunctionwith the term “comprising” in the claims and/or the specification canmean “one,” but it is also consistent with the meaning of “one or more,”“at least one,” and “one or more than one.” Still further, the terms“having,” “including,” “containing,” and “comprising” areinterchangeable, and one of skill in the art is cognizant that theseterms are open-ended terms.

As used herein, “and/or” refers to and encompasses any and all possiblecombinations of one or more of the associated listed items.

The term “about” or “approximately” means within an acceptable errorrange for the particular value as determined by one of ordinary skill inthe art, which will depend in part on how the value is measured ordetermined, i.e., the limitations of the measurement system. Forexample, “about” can mean a range of up to 20%, up to 15%, up to 10%, upto 5%, up to 1%, up to 0.5%, or even up to 0.1% of a given value.

As used herein, a “therapeutically effective,” “therapeutic,” or“therapeutically acceptable” amount refers to an amount that will elicita therapeutically useful response in a subject and includes anadditional amount or overage of active ingredient deemed necessary inthe formulation to provide the desired amount upon administration. Thetherapeutically useful response can provide some alleviation,mitigation, and/or decrease in at least one clinical symptom in thesubject. Those skilled in the art will appreciate that thetherapeutically useful response need not be complete or curative, aslong as some benefit is provided to the subject. In some embodiments,the subject is a human. In certain embodiments, a “therapeuticallyeffective,” “therapeutic,” or “therapeutically acceptable” amount refersto a dose that produces a plasma level of THP, or a pharmaceuticallyacceptable salt thereof, from about 1 ng/ml to about 20 ng/ml, based onthe strength of the THP composition.

As used herein, the term “drug recovery” refers to percentage of thetotal amount of drug present in the dosage form that is released in adissolution medium. The term “complete drug recovery” refers to releaseof about 90% to about 105% of the drug present in the dosage form.

The term “burst release,” as used herein, refers to release of THP or asalt thereof in an amount that is outside (i.e., above) the therapeuticrange of THP, and providing the drug plasma concentration level that canresult in various unwanted side effects. The term “therapeutic range”includes a range of the amount of drug that will elicit atherapeutically useful response in a subject and includes an additionalamount or overage of active ingredient deemed necessary in theformulation to provide the desired amount upon administration.

As used herein, the terms “drug layer,” “drug layer-1,” and “first druglayer,” as used interchangeably herein, refer to one or more layers/druglayers (e.g., at least one drug layer) comprising THP or apharmaceutically acceptable salt thereof. In certain embodiments, thedrug layer-1 is located between the acid core and the functional coatingand provides extended release of THP or a pharmaceutically acceptablesalt thereof. Likewise, the terms “drug layer-2” and “second druglayer,” as used interchangeably herein, refer to one or more drug layerscomprising THP or a pharmaceutically acceptable salt thereof. In certainembodiments, drug layer-2 is located above and covering at least aportion of the functional coat and provides an immediate release of THPor a pharmaceutically acceptable salt thereof. In certain embodiments inwhich only one drug layer is present, that drug layer will be druglayer-1.

The term “coating weight gain”, as used herein, refers to coating weightgain with respect to the weight of the uncoated tablet. For example, acoating weight gain of 15% refers to a 15% w/w increase in tablet weightduring coating with respect to the uncoated tablet weight.

As used herein, the terms “extended release” and “sustained release” areused interchangeably and refer to dosage forms or compositions that areformulated to maintain relatively consistent drug concentrations inplasma during a dosing interval comprising an extended period of time(i.e., post-administration), as compared to the drug administered as animmediate release dosage form. The extended release/sustained releasedosage forms allow the drug to be available over an extended period oftime after administration, thereby allowing a reduction in dosingfrequency, as compared to a drug presented as an immediate releasedosage form.

The term “release rate”, as used herein, refers to the quantity of drugreleased per unit time, e.g., mg of drug released per hour (mg/hour),from a dosage form. In certain embodiments, drug release rates can becalculated under in vitro dosage form dissolution testing conditionsknown in the art.

The term “immediate release,” as used herein, refers to release of atleast 70% of a drug in about one hour or less, preferably within 30minutes or less, post-administration.

The term “semipermeable,” as used herein, refers to a membranecontaining sparingly soluble polymers, or insoluble polymers, with orwithout a pore former(s) that will allow fluids to pass through membraneby diffusion. The permeability of the membranes increases with thedissolution of the pore former(s). As used herein, the terms functionalcoat and semipermeable membrane are used interchangeably.

The terms “pore former” and the like, as used herein, refer topH-dependent or pH-independent water-soluble polymers and/orwater-soluble small molecules that will form pores or channels (i.e.,behave as a channeling agent) in a coating, e.g., functionalcoat/membrane, thereby creating a permeable functional coat/membrane.The term “pore former” includes molecules used to create a certainamount of diffusion through the semipermeable membrane/coating of atablet, pellet, or particle to achieve a sustained release profile. Incertain embodiments, the pore former includes nonionic water-solublepolymers. In certain embodiments, the pore former includes entericpolymers.

The terms “core,” “acid core,” “organic acid core,” “core comprising anorganic acid,” or “core comprising at least one organic acid,” as usedinterchangeably herein, refer to a core (e.g., pellet, bead/seed, orgranule) comprising at least one organic acid; a core (e.g., pellet,bead/seed, or granule) coated with at least one coating comprising atleast one organic acid; or a core that is an organic acid or a mixtureof organic acids.

The term “acid coated core” refers to an inert substrate/non-pareilseed, which is layered/coated with at least one coating comprising atleast one organic acid.

In certain embodiments, the terms “inert substrate,” and “non-pareilseed,” as used interchangeably herein, refers to inertmaterial/particles, e.g., pellets, beads, seeds, or granules. In certainembodiments, the non-pareil seeds are composed of inert substrates suchas starch, sugar, lactose, and/or cellulose. In certain embodiments, thenon-pareil seeds comprise sugar spheres or microcrystallinecellulose/cellets.

The terms “gastric fluid,” and “GI fluid,” as used interchangeablyherein, refer to medium occurring in the stomach and lowergastrointestinal tract of an individual.

The terms “simulated gastric fluid,” and “SGF,” as used interchangeablyherein, refers to a medium that is used to mimic the chemicalenvironment of gastric fluid/medium in an in vitro setting.

As used herein, the term “dissolution medium” refers to a medium used tomimic pH of gastric fluid/medium in stomach or lower gastrointestinaltract of an individual. In certain embodiments, the medium used to mimicchemical environment of stomach of an individual includes a medium withpH of less than about 5.5, e.g., about 1, about 1.25, about 1.5, about1.75, about 2, about 2.25, about 2.5, about 2.75, about 3, about 3.25,about 3.5, about 3.75, about 4.0, about 4.25, about 4.5, about 4.75,about 5.0, about 5.5, or any intermediate values therein. In certainembodiments, the medium used to mimic chemical environment of lower GItract of an individual includes a medium with pH of from about 5.5 toabout 8, e.g., about 5.5, about 5.75, about 6.0, about 6.25, pH 6.5,about 6.75, about 7, about 7.25, about 7.5, or any intermediate valuestherein.

The term “bioavailability” refers to the fraction of an administereddose of unchanged drug that reaches the systemic circulation.

The term “substantially free,” as used herein, refers to an amountcomprising less than 0.001 wt % of the material.

The term “microenvironment,” as used herein, refers to immediateenvironment of the drug, e.g., THP or a pharmaceutically acceptable saltthereof, within the pellet.

The term “acid microenvironment” refers to immediate drug environment(e.g., microenvironment of THP or a pharmaceutically acceptable saltthereof) with a pH of less than about 5.

As used herein, the term “therapeutic concentration” refers to a plasmaconcentration of THP or a pharmaceutically acceptable salt thereof fromabout 1 ng/ml to about 20 ng/ml, based on the strength of thecomposition and the condition.

The terms “Fluctuation Index” and “FI,” as used interchangeably hereinwith respect to the trihexyphenidyl compositions refer to fluctuationsin plasma levels of trihexyphenidyl or a pharmaceutically acceptablesalt thereof released from the composition during a 24-hour dosingperiod. Fluctuation Index provides a quantitative measurement offluctuation in drug plasma concentration, measured as dose relatedpeak-to-trough fluctuations. Fluctuation Index is calculated using theformula: FI=(Cmax−Cmin)/Cav, wherein Cmax is the maximum plasmaconcentration of the drug, e.g., trihexyphenidyl or a pharmaceuticallyacceptable salt thereof; Cmin is the minimum plasma concentration of thedrug; and Cav is the average plasma concentration of the drug. The term“Cav,” as used herein with respect to the trihexyphenidyl compositions,for example marketed IR trihexyphenidyl tablets, e.g., Artane IR (5 mgBID), and Artane IR (2 mg TID), and compositions of the disclosure,refers to average plasma concentration of trihexyphenidyl or apharmaceutically acceptable salt thereof, during a 24-hour dosingperiod.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, and/or inhibiting theprogress of a disease or disorder as described herein. In someembodiments, treatment can be administered after one or more symptomshave developed. In other embodiments, treatment can be administered inthe absence of symptoms. For example, treatment can be administered to asusceptible individual prior to the onset of symptoms (e.g., in light ofa history of symptoms and/or in light of genetic or other susceptibilityfactors). Treatment can also be continued after symptoms have resolved,for example to prevent or delay their recurrence.

As used herein, the terms “trihexyphenidyl” and “trihexyphenidylhydrochloride” are used interchangeably herein. The term“trihexyphenidyl” includes all pharmaceutically acceptable salts,esters, and functionally equivalent chemical compounds, includingtrihexyphenidyl hydrochloride.

As used herein, the terms “up,” “down,” “above,” “below,” “top,”“bottom,” etc. should be interpreted as nonlimiting upon the pellets,cores, layers, methods, and products of any methods of presentdisclosure, which can be spatially arranged in any orientation ormanner.

6.2. Formulations of Pellet Dosage Forms

The present disclosure provides extended release oral trihexyphenidylcompositions that maintain solubility of the drug in different pHenvironments of the GI tract and maintain at least a minimum therapeuticplasma concentration of the drug for extended periods of time, withoutan initial spike or burst in release of the drug.

Trihexyphenidyl is commonly prescribed as trihexyphenidyl hydrochloride.However, use of other pharmaceutically acceptable salts oftrihexyphenidyl is also contemplated in the present disclosure.

Pharmaceutically acceptable salts of trihexyphenidyl known in the artinclude, but are not limited to, hydrochloride, hydrobromide,hydroiodide, bromide, sulfite, sulfate, bisulfate, nitrate, salicylate,citrate, tartrate, bitartrate, lactate, phosphate, malate, maleate,fumarate, succinate, acetate, and pamoate salts.

In certain embodiments, the present disclosure provides for compositionsthat comprise THP and are able to maintain plasma concentrations of THPat about 80% of C_(max) for an average time period of about 6 hours, atabout 70% of C_(max) for an average time period of about 8 hours, atabout 60% of C_(max) for an average time period of about 12 hours, andat about 50% of C_(max) value for an average time period of about 24hours post-administration of the extended release THP composition,compared with values of about 80% of C_(max) at 3 hours, about 70% ofC_(max) at 4 hours, and about 30% C_(max) at about 8 hourspost-administration of an immediate release THP composition.

In certain embodiments, compositions of the present disclosure compriseTHP extended release pellets. In certain embodiments, the compositionsdescribed herein comprise capsules containing extended release pellets.In certain embodiments, the extended release pellets comprise an acidcore coated with a seal coat, a drug layer over the seal coat, and afunctional coat/membrane over the drug-layered core. In certainembodiments, the presence of seal coat is optional. In certainembodiments, the acid core is a nonpareil seed (e.g.,cellet/microcrystalline cellulose, sugar sphere) layered with at leastone coating layer comprising at least one organic acid. In certainembodiments, the compositions of the disclosure comprise at least oneimmediate release drug layer (drug layer-2) over the functional coat. Incertain embodiments, the compositions of the disclosure comprise a sealcoat (seal coat-2) between the functional coat and drug layer-2. Incertain embodiments, the compositions of the disclosure comprise an overcoat over drug layer-2. In certain embodiments, the presence of sealcoat-2 and/or over coat is optional. Each component of the compositionsof the present disclosure is described in more detail below.

In certain embodiments, the present disclosure provides pelletscomprising a core that comprises at least one organic acid. The organicacid in the core provides an acidic microenvironment aroundtrihexyphenidyl to increase solubility of trihexyphenidyl, which is aweak base with poor solubility at a pH of greater than or equal to about5. In certain embodiments, the core is spherical or irregular in shape.In certain embodiments, the core is a pellet, bead/seed, or a granulecomprising at least one organic acid. In certain embodiments, the coreis a pellet, bead/seed, or a granule coated with at least one coatingcomprising at least one organic acid. In certain embodiments, the coreis an organic acid or a mixture of organic acids. In a specificembodiment, organic acid granules are used as the core. In certainembodiments, the core is an acid coated core comprising a nonpareil seedcoated with at least one coating comprising at least one organic acid,e.g., a cellet/sugar sphere coated with an organic acid. In certainembodiments, the core is a microcrystalline cellulose sphere, or a sugarsphere coated with at least one coating comprising at least one organicacid. In certain embodiments, the organic acid coat over the nonpareilseed contains trihexyphenidyl or a pharmaceutically acceptable saltthereof. In certain embodiments, the organic acid core is coated with acoat containing trihexyphenidyl or a pharmaceutically acceptable saltthereof, and at least one additional organic acid. In certainembodiments, the additional organic acid in the coating can be same asthe organic acid present in the core. In certain embodiments, theadditional organic acid in the coating can be different from the organicacid present in the core.

In certain embodiments, the organic acid in the core provides acidmicroenvironment for protonating trihexyphenidyl in alkaline pH presentin the lower GI tract, e.g., intestine. As protonated THP is moresoluble than THP free base, therapeutic plasma concentrations of the THPare maintained as the dosage form travels through the intestine. Incertain embodiments, the organic acid in the core improves in vivosolubility and plasma levels of the THP. In certain embodiments, thecompositions of the present disclosure maintain a therapeuticallyeffective plasma concentration of trihexyphenidyl for extended timeperiods.

Without being bound to any particular theory, the organic acid in thecore is believed to enhance the dissolution and absorption oftrihexyphenidyl throughout the GI tract, especially in the lower GItract with pH of >5. The organic acid in the core lowers themicroenvironmental pH within the pellet and solubilizes THP. As themicroenvironmental pH within the pellet drops, the trihexyphenidyl isprotonated and solubilized for absorption in the GI tract.

In certain embodiments, the core consists of one or more organic acids.In certain embodiments, the organic acid in the core is present in anamount of from about 5% to about 100%, from about 20% to about 80%, fromabout 30% to about 70% w/w, or any intermediate values thereof, based onthe total weight of the core. In certain embodiments, the organic acidis present in amount of at least about 5%, at least about 10%, at leastabout 15%, at least about 20%, at least about 25%, at least about 30%,at least about 35%, at least about 40%, at least about 45%, at leastabout 50%, at least about 55%, at least about 60%, at least about 65%,at least about 70%, at least about 75%, at least about 80%, at leastabout 85%, at least about 90%, or 100% w/w, based on the total weight ofthe core.

In certain embodiments, the core makes up from about 40% to about 99%,from about 50% to about 95%, from about 60% to about 90% w/w, or anyintermediate values thereof, of the total weight of the composition ofthe present disclosure. In certain embodiments, the core makes up atleast about 40%, at least about 42.5%, at least about 45%, at leastabout 47.5%, at least about 50%, at least about 52.5%, at least about55%, at least about 57.5%, at least about 60%, at least about 62.5%, atleast about 65%, at least about 67.5%, at least about 70%, at leastabout 72.5%, at least about 75%, at least about 77.5%, at least about80%, at least about 82.5%, at least about 85%, at least about 87.5%, atleast about 90% w/w, at least about 92.5%, at least about 95%, at leastabout 97.5%, or at least about 99% w/w, of the total weight of thecomposition of the present disclosure.

In certain embodiments, the organic acid is one or more of tartaricacid, citric acid, fumaric acid, succinic acid, malic acid, or anycombinations thereof. In certain embodiments, the organic acid iscrystalline tartaric acid.

In certain embodiments, the compositions of the present disclosureprovide excellent stability and bioavailability of trihexyphenidylhydrochloride for extended periods of time. The excellent stability andbioavailability of trihexyphenidyl hydrochloride is at least in partprovided by the presence of an organic acid that ensures trihexyphenidylremains solubilized for extended periods of time after oraladministration, even in a weakly acidic, neutral, or basic environment.

6.2.2. Seal Coats and Over Coat

In certain embodiments, the core is coated with at least one seal coat.In certain embodiments, the seal coat is optional. In certainembodiments, the pellets can include two seal coats (seal coat-1 betweenthe core and drug layer-1, and the seal coat-2 between the functionalcoat and drug layer-2). In certain embodiments, the pellets include atleast one over coat. In certain embodiments, the presence of seal coat-2and/or the overcoat is optional. In certain embodiments, pelletscontaining one drug layer (e.g., drug layer-1) do not contain sealcoat-2 and over coat. In certain embodiments, the pellets containingdrug layer-1 include various components and coats in the followingorder: a core; seal coat-1 over the core and covering at least a portionof the core; drug layer-1, containing THP for extended release, overseal coat-1 and covering at least a portion of seal coat-1; and afunctional coat over drug layer-1 and covering at least a portion ofdrug layer-1. In certain embodiments, the pellets containing druglayer-1 further include seal coat-2 over the functional coat. In certainembodiments, the pellets containing drug layer-1 further include an overcoat over seal coat-2. In certain embodiments, the pellets containing atdrug layer-1 and drug layer-2 include various components and coats inthe following order: a core; seal coat-1 over the core and covering atleast a portion of the core; drug layer-1, containing THP for extendedrelease, over seal coat-1 and covering at least a portion of sealcoat-1; and a functional coat over drug layer-1 and covering at least aportion of drug layer-1, seal coat-2 over the functional coat andcovering at least a portion of the functional coat; drug layer-2,containing THP for immediate release, over seal coat-2 and covering atleast a portion of seal coat-2; and an overcoat over drug layer-2 andcovering at least a portion of drug layer-2. In certain embodiments, theeach of the seal coat-1, the seal coat-2, and/or the over coat arepresent at a coating weight gain of between 0% and about 10% w/w, basedon the total weight of the corresponding pellet without thecorresponding coats (e.g., pellets without seal coat-1, seal coat-2,and/or the over coat). In certain embodiments, each of the seal coat-1,the seal coat-2, and/or the over coat are present at a coating weightgain of about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%,about 6%, about 7%, about 8%, about 9%, about 10% w/w, or anyintermediate values therein, based on the total weight of thecorresponding pellet without seal coat-1, seal coat-2, and/or the overcoat. In certain embodiments, coating solvents used for coating the sealcoat and/or the over coat comprise, but are not limited to, an organicsolvent, water, and/or any mixtures thereof. In certain embodiments, thecoating solvent is a mixture of an organic solvent and water. In certainembodiments, organic solvent:water weight ratio is between 60:40 and98:2. In certain embodiments, the organic solvent:water weight ratio isabout 60:40, about 70:30, about 75:25, 80:20, about 85:15, about 90:10,about 95:5, about 98:2, or any intermediate values therein. In certainembodiments, the coating solvents comprise organic solvents selectedfrom the group consisting of methylene chloride, carbon tetrachloride,acetone, methanol, ethanol 200 proof, and/or any mixtures thereof. Incertain embodiments, coating solvents comprise, but are not limited to,methylene chloride, carbon tetrachloride, acetone, methanol, ethanol 200proof, water, and/or any mixtures thereof. In certain embodiments, thecoating solvent is a mixture of ethanol 200 proof and water. In certainembodiments, ethanol:water weight ratio is between 60:40 and 98:2. Incertain embodiments, the ethanol:water weight ratio is about 60:40,about 70:30, about 75:25, 80:20, about 85:15, about 90:10, about 95:5,about 98:2, or any intermediate values therein.

In certain embodiments, the seal coat(s) and over coat comprise anonionic water-soluble polymer. In certain embodiments, the nonionicwater-soluble polymer is selected from a group comprising hydroxypropylcellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, polyethylene glycol, polyvinyl alcohol, poloxamer, polyvinylpyrrolidone-vinyl acetate copolymer (e.g., copovidone), and mixturesthereof. In certain embodiments, the amount of the nonionicwater-soluble polymer ranges from about 5% to about 100% w/w, based onthe total weight of the seal coat/over coat composition. In certainembodiments, the amount of the nonionic water-soluble polymer rangesfrom about 10% to about 95%, from about 15% to about 90%, from about 20%to about 85%, from about 25% to about 80%, from about 30% to about 75%,from about 35% to about 70%, from about 40% to about 65%, from about 45%to about 60%, or from about 50% to about 55% w/w, based on the totalweight of the seal coat/over coat composition. In certain embodiments,the nonionic water-soluble polymer is present in an amount of about 70%,about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about77%, about 78%, about 79%, about 80% w/w, or any intermediate valuestherein, based on the total weight of the seal coat/over coatcomposition.

In certain embodiments, the composition of the seal coat/over coatfurther comprises additional excipients, such as anti-tacking agentsand/or plasticizers. In certain embodiments, anti-tacking agentsinclude, but are not limited to, silicon dioxide (SYLOID® 244FP), fumedsilica (CAB-O-SIL®), talc, kaolin, magnesium trisilicate, powderedstarch, tribasic calcium phosphate, and any combinations thereof. Incertain embodiments, the anti-tacking agent can be present in an amountof from about 5% to about 35% w/w, based on the total weight of thenonionic water-soluble polymer present in the seal coat/over coatcomposition. In certain embodiments, the anti-tacking agent is presentin an amount of about 5%, about 6%, about 7%, about 8%, about 9%, about10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%,about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%,about 30%, about 31%, about 32%, about 33%, about 34%, about 35% w/w, orany intermediate values therein, based on the total weight of thenonionic water-soluble polymer present in the seal coat/overcoatcomposition. In certain embodiments, the plasticizers include, but arenot limited to, glycerin, polyethylene glycol monomethyl ether, triethylcitrate, triacetin, polyethylene glycol, propylene glycol, sorbitolsorbitan solution, dibutyl sebacate, or mixtures thereof. In certainembodiments, the plasticizer is triethyl citrate. In certainembodiments, the plasticizer is dibutyl sebacate. In certainembodiments, the plasticizer is present in an amount of about 0%, about1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%,about 15%, about 16%, about 17%, about 18%, about 19%, about 20% w/w, orany intermediate values therein, based on the total weight of thenonionic water-soluble polymer present in the seal coat/over coatcomposition. In certain embodiments, the seal coat/over coat issubstantially free of a plasticizer. In certain embodiments, the amountof the additional excipients, when present, can range from about 0.1% toabout 40%, from about 1% to about 35%, from about 2% to about 30%, fromabout 3% to about 25%, or from about 4% to about 20% w/w, based on thetotal weight of the nonionic water-soluble polymer; and in someembodiments from about 0.5% to about 25% w/w, based on the total weightof the nonionic water-soluble polymer present in the seal coat/over coatcomposition. In certain embodiments, the additional excipients arepresent in amount of at least about 1%, at least about 5%, at leastabout 10%, at least about 15%, at least about 20%, at least about 25%,at least about 30% w/w, at least about 35%, or any intermediate valuestherein, based on the total weight of the nonionic water-soluble polymerpresent in the seal coat/over coat composition.

6.2.3. Drug Layer

In certain embodiments, the core or a core coated with at least one sealcoat is further coated with at least one drug layer. In certainembodiments, the drug layer covers at least a portion of the core. Incertain embodiments, the drug layer comprises trihexyphenidyl or apharmaceutically acceptable salt thereof and a nonionic water-solublepolymer. In certain embodiments, the drug layer further comprises atleast one organic acid. In certain embodiments, the organic acidincludes, but is not limited to, tartaric acid, citric acid, fumaricacid, succinic acid, malic acid, and mixtures thereof. In certainembodiments, coating solvents used for coating the drug layer comprise,but are not limited to, an organic solvent, water, and/or any mixturesthereof. In certain embodiments, the coating solvent is a mixture of anorganic solvent and water. In certain embodiments, organic solvent:waterweight ratio is between 60:40 and 98:2. In certain embodiments, theorganic solvent:water weight ratio is about 60:40, about 70:30, about75:25, 80:20, about 85:15, about 90:10, about 95:5, about 98:2, or anyintermediate values therein. In certain embodiments, the coatingsolvents comprise organic solvents selected from the group consisting ofmethylene chloride, carbon tetrachloride, acetone, methanol, ethanol 200proof, and/or any mixtures thereof. In certain embodiments, coatingsolvents comprise, but are not limited to, methylene chloride, carbontetrachloride, acetone, methanol, ethanol 200 proof, water, and/or anymixtures thereof. In certain embodiments, the coating solvent is amixture of ethanol 200 proof and water. In certain embodiments,ethanol:water weight ratio is between 60:40 and 98:2. In certainembodiments, the ethanol:water weight ratio is about 60:40, about 70:30,about 75:25, 80:20, about 85:15, about 90:10, about 95:5, about 98:2, orany intermediate values therein.

In certain embodiments, the pellets comprise at least one first druglayer, which is an extended release drug layer (drug layer-1) and atleast one second drug layer, which is an immediate release drug layer(drug layer-2). In certain embodiments, drug layer-1 can comprise one ormore drug layers. In certain embodiments, drug layer-2 can comprise oneor more drug layers. In certain embodiments, the weight ratio oftrihexyphenidyl or a pharmaceutically acceptable salt thereof in theextended release drug layer-1 and the immediate release drug layer-2 isfrom about 70:30 to about 100:0. In certain embodiments, the weightratio of trihexyphenidyl or a pharmaceutically acceptable salt thereofin the extended release drug layer-1 and the immediate release druglayer-2 is about 70:30, about 75:25, about 80:20, about 85:15, about90:10, about 95:5, about 100:0, or any intermediate ratios therein. Incertain embodiments, drug layer-1 is positioned between seal coat-1 andthe functional coat. In certain embodiments, there is no seal coatbetween the core and drug layer-1. In certain embodiments, thefunctional coat controls the release of trihexyphenidyl or apharmaceutically acceptable salt thereof from drug layer-1. In certainembodiments, drug layer-2 is positioned between seal coat-2 and the overcoat. In certain embodiments, there is no seal coat-2 between thefunctional coat and drug layer-2.

In certain embodiments, drug layer-1 comprises from about 1 mg to about20 mg of trihexyphenidyl or a pharmaceutically acceptable salt thereof.In certain embodiments, the drug layer-1 comprises about 1 mg, about 2mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg,about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about19 mg, about 20 mg, or any intermediate values therein, oftrihexyphenidyl pr a pharmaceutically acceptable salt thereof. Incertain embodiments, drug layer-2 comprises from about 0 mg to about 1.5mg of trihexyphenidyl or a pharmaceutically acceptable salt thereof. Incertain embodiments, drug layer-2 comprises about 0.1 mg, 0.2 mg, about0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3mg, about 1.4 mg, about 1.5 mg, or any intermediate values therein, oftrihexyphenidyl or a pharmaceutically acceptable salt thereof. Incertain embodiments, the trihexyphenidyl or a pharmaceuticallyacceptable salt thereof is present in a concentration of from about 10%to about 70%, from about 15% to about 65%, from about 20% to about 60%,from about 25% to about 55%, or from about 30% to about 50% w/w, basedon the total weight of the drug layer (drug layer-1 and drug layer-2)composition. In certain embodiments trihexyphenidyl or apharmaceutically acceptable salt thereof is present in a concentrationof from about 10% to about 80% w/w, based on the total weight of druglayer-1. In certain embodiments trihexyphenidyl or a pharmaceuticallyacceptable salt thereof is present in a concentration of about 20%,about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%,about 58%, about 59%, about 60%, about 65%, about 70%, about 75%, about80% w/w, or any intermediate values therein, based on the total weightof the drug layer-1 (extended release drug layer) composition. Incertain embodiments trihexyphenidyl or a pharmaceutically acceptablesalt thereof is present in a concentration of from about 5% to about 50%w/w, based on the total weight of drug layer-2 composition. In certainembodiments trihexyphenidyl or a pharmaceutically acceptable saltthereof is present in a concentration of about 5%, about 10%, 15%, about20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%w/w, or any intermediate values therein, based on the total weight ofthe drug layer-2 (immediate release drug layer) composition. In certainembodiments, trihexyphenidyl or a pharmaceutically acceptable saltthereof is present in a concentration of from about 1% w/w to about 10%w/w, based on the total weight of the composition.

In certain embodiments, the weight ratio of trihexyphenidyl or apharmaceutically acceptable salt thereof to the organic acid is fromabout 1:1 to about 1:100, from about 1:1 to about 1:90, from about 11 toabout 1:80, from about 1:1 to about 1:70, from about 1:1 to about 1:60,from about 1:1 to about 1:50, from about 1:1 to about 1:40, from about1:1 to about 1:30, from about 1:1 to about 1:20, from about 1:1 to about1:10, or any intermediate values therein, by weight. In certainembodiments, the weight ratio of trihexyphenidyl or a pharmaceuticallyacceptable salt thereof to the organic acid is about 1:50, about 1:47.7,about 1:45, about 1:42.5, about 1:40, about 1:37.5, about 1:35, about1:32.5, about 1:30, about 1:29, about 1:28, about 1:27, about 1:26,about 1:25, about 1:24, about 1:23, about 1:22, about 1:21, about 1:20,about 1:19, about 1:18, about 1:17, about 1:16, about 1:15, about 1:14,about 1:13, about 1:12, about 1:11, about 1:10, about 1:9, about 1:8,about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, about1:1, or any intermediate ratios thereof.

In certain embodiments, the drug layer (drug layer-1 and/or druglayer-2) comprises a nonionic water-soluble polymer. In certainembodiments, the nonionic water-soluble polymer in the drug layer isselected from the group consisting of hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose,polyethylene glycol, polyvinyl alcohol, poloxamer, polyvinylpyrrolidone-vinyl acetate copolymer (e.g., copovidone), and mixturesthereof. In certain embodiments, the amount of the nonionicwater-soluble polymer ranges from about 5% to about 95%, from about 10%to about 90%, about 20% to about 80%, from about 30% to about 70%, fromabout 40% to about 60%, or from about 45% to about 55% w/w, based on thetotal weight of the drug layer composition. In certain embodiments, theconcentration of the nonionic water-soluble polymer ranges from about10% to about 40%, e.g., about 11%, about 12%, about 13%, about 14%,about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%,about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about34%, about 35%, about 36%, about 37%, about 38%, and about 39% w/w, orintermediate values thereof, based on the total weight of the drug layercomposition. In certain embodiments, the concentration of the nonionicwater-soluble polymer in drug layer-1 ranges from about 10% to about 40%w/w, based on the total weight of the drug layer-1 composition. Incertain embodiments, the concentration of the nonionic water-solublepolymer in drug layer-1 is about 10%, about 20%, about 30%, about 31%,about 32%, about 33%, about 34%, about 35% w/w, about 36%, about 37%,about 38%, about 39%, about 40% w/w, or any intermediate values therein,based on the total weight of the drug layer-1 composition. In certainembodiments, the concentration of the nonionic water-soluble polymer indrug layer-2 ranges from about 10% to about 40% w/w, based on the totalweight of the drug layer-2 composition. In certain embodiments, theconcentration of the nonionic water-soluble polymer in drug layer-2 isabout 10%, about 11%, about 12%, about 13%, about 14%, about 15% w/w,about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%,about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about35%, about 36%, about 37%, about 38%, about 39%, about 40% w/w, or anyintermediate values therein, based on the total weight of the druglayer-2 composition.

In certain embodiments, the drug layer(s) further includes additionalexcipients comprising anti-tacking agents, and/or plasticizers. Incertain embodiments, anti-tacking agents include, but are not limitedto, silicon dioxide (SYLOID® 244FP), fumed silica (CAB-O-SIL®), talc,kaolin, magnesium trisilicate, powdered starch, and/or tribasic calciumphosphate. In certain embodiments, the anti-tacking agent can be presentin an amount of about 5% to about 100% w/w, based on the total weight ofthe nonionic water-soluble polymer present in the drug layercomposition. In certain embodiments, the anti-tacking agent is presentin an amount of about 10% w/w, about 15%, about 20%, about 25%, about30%, about 35, about 40%, about 45%, about 50%, about 55%, about 60%,about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% w/w,based on the total weight of the nonionic water-soluble polymer presentin the drug layer composition.

In certain embodiments, the plasticizers include, but are not limitedto, glycerin, triethyl citrate, triacetin, polyethylene glycol,propylene glycol, sorbitol sorbitan solution, and/or dibutyl sebacate.In certain embodiments, the plasticizer is triethyl citrate. In certainembodiments, the plasticizer is dibutyl sebacate. In certainembodiments, the plasticizer is present in an amount of about 0%, about0.1%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%,about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about20% w/w, or any intermediate values therein, based on the total weightof nonionic water-soluble polymer present in the drug layer composition.In certain embodiments, the total amount of the additional excipients ispresent in a range from about 0.1% to about 100%, from about 1% to about50%, from about 2% to about 40%, from about 3% to about 35%, from about4% to about 30%, from about 5% to about 25%, or from about 6% to about20% w/w, based on the total weight of the nonionic water-soluble polymerpresent in the drug layer composition.

In certain embodiments, the drug layer (e.g., drug layer-1 and/or druglayer-2) comprise at least one organic acid to solubilizetrihexyphenidyl. In certain embodiments, the immediate release druglayer, e.g., drug layer-2, comprises at least one organic acid. Incertain embodiments, drug layer-1 (extended release drug layer) does notrequire any organic acid as the drug layer is in close proximity to thecore comprising organic acid. In certain embodiments, drug layer-1 doesnot comprise an organic acid, and drug layer-2 comprises an organicacid. In certain embodiments, the organic acid comprises tartaric acid,citric acid, fumaric acid, succinic acid, malic acid, or anycombinations thereof. In certain embodiments, the organic acid in druglayer-2 is different from the organic acid in the core. In certainembodiments, the organic acid in the core is tartaric acid and theorganic acid in drug layer-2 is succinic acid. In certain embodiments,the organic acid in the core and drug layer-2 is tartaric acid and/orsuccinic acid.

6.2.4. Functional Coat/Extended Release Layer/Membrane

In certain embodiments, the drug-layered pellet is further coated with afunctional coat comprising a water-insoluble polymer, a plasticizer, anda pore former. In certain embodiment, the functional coat can compriseat least one functional coat. In certain embodiments, there is a sealcoat between the drug layer (drug layer-1) and the functional coat. Incertain embodiments, the functional coat covers at least a portion ofthe drug layer (e.g., drug layer-1). In certain embodiments, the pelletscomprising drug layer-1 (extended release drug layer) and drug layer-2(immediate release drug layer) contain seal coat-1 between the core anddug layer-1; functional coat over drug layer-1; and seal coat-2 betweenfunctional coat and drug layer-2. In certain embodiments, coatingsolvents used for coating the functional coat comprise, but are notlimited to, an organic solvent, water, and/or any mixtures thereof. Incertain embodiments, the coating solvent is a mixture of an organicsolvent and water. In certain embodiments, organic solvent:water weightratio is between 60:40 and 98:2. In certain embodiments, the organicsolvent:water weight ratio is about 60:40, about 70:30, about 75:25,80:20, about 85:15, about 90:10, about 95:5, about 98:2, or anyintermediate values therein. In certain embodiments, the coatingsolvents comprise organic solvents selected from the group consisting ofmethylene chloride, carbon tetrachloride, acetone, methanol, ethanol 200proof, and/or any mixtures thereof. In certain embodiments, coatingsolvents comprise, but are not limited to, methylene chloride, carbontetrachloride, acetone, methanol, ethanol 200 proof, water, and/or anymixtures thereof. In certain embodiments, the coating solvent is amixture of ethanol 200 proof and water. In certain embodiments,ethanol:water weight ratio is between 60:40 and 98:2. In certainembodiments, the ethanol:water weight ratio is about 60:40, about 70:30,about 75:25, 80:20, about 85:15, about 90:10, about 95:5, about 98:2, orany intermediate values therein.

In certain embodiments, the functional coat has a coating weight gain offrom about 5% to about 50% w/w, based on the total weight of the pelletwithout functional coat. In certain embodiments, the functional coat hasa coating weight gain of about 5%, about 6%, about 7%, about 8%, about9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%,about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%,about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%,about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about48%, about 49%, about 50% w/w, or any intermediate values therein, basedon the total weight of the pellet without functional coat.

In certain embodiments, the functional coat comprises a water-insolublepolymer, a plasticizer, a pore former, and an anti-tacking agent. Incertain embodiments, the functional coat includes a water-solublepolymer as a pore former. In certain embodiments, the water-solublepolymer is an enteric polymer. In certain embodiments, the entericpolymer used as a pore former comprises, but is not limited to,cellulose acetate phthalate, cellulose acetate succinate,methylcellulose phthalate, hydroxyethyl cellulose phthalate, polyvinylacetate phthalate, polyvinyl butyrate acetate, vinyl acetate-maleicanhydride copolymer, hydroxypropyl methylcellulose phthalate, polyvinylacetate phthalate, cellulose acetyl phthalate, methacrylic acid andmethyl methacrylate (1:2) copolymer (EUDRAGIT® S 100), methacrylic acidand methyl methacrylate (1:1) copolymer (EUDRAGIT L®100), methacrylicacid and methyl methacrylate (1:2) copolymer solution (EUDRAGIT® S12.5), methacrylic acid and methyl methacrylate (1:1) copolymer solution(EUDRAGIT® L 12.5), and combinations thereof. In certain embodiments,the pore former is a nonionic pH-independent water-soluble polymercomprising, but not limited to, methyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose,polyethylene glycol, polyvinyl alcohol, poloxamer, and mixtures thereof.

In certain embodiments, the water-insoluble polymer in the functionalcoat comprises, but is not limited to, ethyl cellulose (ETHOCEL™),cellulose acetate, cellulose diacetate, cellulose triacetate, cellulosepropionate, a polyvinyl acetate dispersion (KOLLICOAT® SR), or mixturesthereof.

In certain embodiments, the water-insoluble polymer is present in anamount of from about 20% to about 99%, from about 40% to about 80%, fromabout 50% to about 70%, from about 55% to about 65%, w/w, or anyintermediate value therein, based on the total weight of the functionalcoat. In certain embodiments, the water-insoluble polymer is present inan amount of about 20%, about 25%, about 30%, about 35%, about 40%,about 45%, about 50%, about 55%, about 56%, about 57%, about 58%, about59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%,about 66%, about 67%, about 68%, about 69%, about 70% w/w, or anyintermediate values therein, based on the total weight of the functionalcoat. In certain embodiments, a pore former is present in an amount offrom about 1% to about 50%, from about 10% to about 25%, from about 15%to about 20% w/w, or any intermediate values therein, based on the totalweight of the functional coat. In certain embodiments, a pore former ispresent in an amount of about 1%, about 2%, about 3%, about 4%, 5%,about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%,about 13%, about 14%, about 15% w/w, or any intermediate values therein,based on the total weight of the functional coat. In certainembodiments, the water-insoluble polymer and the pore former are presentin a weight ratio of from about 50:50 to about 98:2. In certainembodiments, the water-insoluble polymer and the pore former are presentin a weight ration of about 50:50, about 55:45, about 60:40, about65:35, about 70:30, about 75:25, about 80:20, about 85:15, about 90:10,about 95:5, about 98:2, or any intermediate values therein.

In certain embodiments, the anti-tacking agents include, but are notlimited to, silicon dioxide (SYLOID® 244FP), fumed silica (CAB-O-SIL®),talc, kaolin, talc, magnesium trisilicate, powdered starch, and/ortribasic calcium phosphate. In certain embodiments, the anti-tackingagent can be present in an amount of from about 5% to about 30% w/w,based on the combined weight of the water-insoluble polymer and the poreformer. In certain embodiments, the anti-tacking agent is present in anamount of about 5%, about 6%, about 7%, about 8%, about 9%, about 10%,about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%,about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about30% w/w, or any intermediate values therein, based on the combinedweight of the water-insoluble polymer and the pore former. In certainembodiments, plasticizers include, but are not limited to, glycerin,polyethylene glycol monomethyl ether, triethyl citrate, triacetin,polyethylene glycol, propylene glycol, sorbitol sorbitan solution,dibutyl sebacate, or mixtures thereof. In certain embodiments, theplasticizer is triethyl citrate. In certain embodiments, the plasticizeris dibutyl sebacate. In certain embodiments, the plasticizer can bepresent in an amount of from about 0.1% to about 20% w/w, based on thecombined weight of the water-insoluble polymer and the pore former. Incertain embodiments, the plasticizer is present in an amount of about0.1%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%,about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about20% w/w, or any intermediate values therein, based on the combinedweight of the water-insoluble polymer and the pore former.

In certain embodiments, the plasticizer acts as a pore former. Incertain embodiments, the weight ratio of water-insoluble polymer andplasticizer determines the release rate of trihexyphenidylhydrochloride. In certain embodiments, the enteric polymer functions asa pore former to release the trihexyphenidyl hydrochloride fluxgenerated due to the presence of an acid microenvironment in the dosageform. In certain embodiments, the presence of (1) an acidmicroenvironment in the core; and (2) at least one water-insolublepolymer and at least one enteric polymer in the functional coat,maintains and controls the release rate of trihexyphenidyl hydrochloridethroughout the GI tract, including the high pH regions of the GI tractwith pH of greater than or equal to about 5.

6.2.5. Pellets

In certain embodiments, the present disclosure provides extended releaseoral trihexyphenidyl hydrochloride pellet compositions that maintainsolubility of the drug in different pH environments of the GI tract, andmaintain at least a minimum therapeutic plasma concentration of the drugfor extended periods of time, without any initial spike or burst inrelease of the drug.

In certain embodiments, the pellets comprise a core comprising at leastone organic acid and coated with a seal coat, a drug layer over the sealcoat, and a functional coat/membrane over the drug-layered core. Incertain embodiments, the pellets comprise a core coated with sealcoat-1, drug layer-1 over seal coat-1, functional coat over druglayer-1, seal coat-2 over functional coat, drug layer-2 over sealcoat-2, and an over coat over drug layer-2. In certain embodiments, thepellets comprise a core coated with seal coat-1, drug layer-1 over sealcoat-1, and functional coat over drug layer-1.

In certain embodiments, the core comprises from about 10 mg to about 200mg, from about 20 mg to about 100 mg, from about 30 mg to about 80 mg,from about 40 mg to about 60 mg, or about 50 mg of an organic acid. Incertain embodiments, the core comprises tartaric acid in an amount offrom about 45% w/w to about 80% w/w, from about 50% w/w to about 75%w/w, from about 55% w/w to about 70% w/w, or from about 60% w/w to about65% w/w, based on the total weight of the composition.

In certain embodiments, the seal coat(s) (i.e., seal coat-1 and sealcoat-2) and/or the over coat comprise from about 0.1 mg to about 10 mg,from about 0.2 mg to about 9.0 mg, from about 0.3 mg to about 8.0 mg,from about 0.4 mg to about 7.5 mg, from about 0.5 mg to about 7.0 mg,from about 1.0 mg to about 6.0 mg, from about 1.5 mg to about 5.0 mg,from about 2.0 mg to about 4.0 mg, from about 2.5 mg to about 3.5 mg, orabout 3.0 mg of hypromellose (METHOCEL® E5 Prem LV). In certainembodiments, the seal coat(s) and/or over coat further comprise fromabout 0.01 mg to about 0.5 mg, from about 0.02 mg to about 0.4 mg, fromabout 0.03 mg to about 0.35 mg, from about 0.05 mg to about 0.25 mg,from about 0.06 mg to about 0.20 mg, from about 0.07 mg to about 0.15mg, or from about 0.08 mg to about 0.10 mg of triethyl citrate. Incertain embodiments, the seal coat(s) and/or over coat also comprisefrom about 0.05 mg to about 2.0 mg, from about 0.1 mg to about 1.5 mg,from about 0.15 mg to about 1.0 mg, from about 0.2 mg to about 0.9 mg,from about 0.25 mg to about 0.8 mg, from about 0.3 mg to about 0.7 mg,from about 0.35 mg to about 0.6 mg, or from about 0.4 mg to about 0.5 mgof talc. In certain embodiments, the seal coat(s) and/or the over coatcomprise hypromellose (METHOCEL® E5 Prem LV) in an amount of from about2.0% w/w to about 5.0% w/w, from about 2.25% w/w to about 4.5% w/w, fromabout 2.5% w/w to about 4.0% w/w, from about 2.75% w/w to about 3.5%w/w, or from about 3.0% w/w to about 3.25% w/w, based on the totalweight of the composition. In certain embodiments, the seal coat(s)and/or over coat further comprise triethyl citrate in an amount of fromabout 0.05% w/w to about 0.30% w/w, from about 0.06% w/w to about 0.25%w/w, from about 0.07% w/w to about 0.24% w/w, from about 0.08% w/w toabout 0.23% w/w, from about 0.09% w/w to about 0.22% w/w, from about0.10% w/w to about 0.21% w/w, from about 0.11% w/w to about 0.20% w/w,from about 0.12% w/w to about 0.19% w/w, from about 0.13% w/w to about0.18% w/w, from about 0.14% w/w to about 0.17% w/w, or from about 0.15%w/w to about 0.16% w/w, based on the total weight of the composition. Incertain embodiments, the seal coat(s) and/or over coat also comprisetalc in an amount of from about 0.5% w/w to about 1.25% w/w, from about0.55% w/w to about 1.20% w/w, from about 0.60% w/w to about 1.15% w/w,from about 0.65% w/w to about 1.10% w/w, from about 0.70% w/w to about1.05% w/w, from about 0.75% w/w to about 1.0% w/w, from about 0.80% w/wto about 0.95% w/w, or from about 0.85% w/w to about 0.90% w/w, based onthe total weight of the dosage form.

In certain embodiments, drug layer-1 and drug layer-2 comprisetrihexyphenidyl hydrochloride, hypromellose, triethyl citrate, and talc.In certain embodiments, drug layer-1 and/or drug layer-2 contain fromabout 0.5 mg to about 10 mg, from about 1.0 mg to about 9.0 mg, fromabout 1.5 mg to about 8.5 mg, from about 2.0 mg to about 8.0 mg, fromabout 2.5 mg to about 7.5 mg, from about 3.0 mg, to about 7.0 mg, fromabout 3.5 mg to about 6.5 mg, from about 4.0 mg to about 6.0 mg, fromabout 4.5 mg to about 5.5 mg, or about 5.0 mg of trihexyphenidylhydrochloride. In certain embodiments, drug layer-1 and/or drug layer-2comprise from about 0.01 mg to about 6.0 mg, from about 0.5 mg to about5.0 mg, from about 1.0 mg to about 4.5 mg, from about 1.5 mg to about4.0 mg, from about 2.0 mg to about 3.5 mg, or from about 2.5 mg to about3.0 mg of hypromellose. In certain embodiments, drug layer-1 and/or druglayer-2 comprise from about 0.001 mg to about 0.3 mg, from about 0.01 mgto about 0.25 mg, from about 0.05 mg to about 0.2 mg, or from about 0.1mg to about 0.15 mg of triethyl citrate. In certain embodiments, druglayer-1 and drug layer-2 comprise from about 0.05 mg to about 2.0 mg,from about 0.1 mg to about 1.5 mg, from about 0.2 mg to about 1.45 mg,from about 0.3 mg to about 1.40 mg, from about 0.4 mg to about 1.35 mg,from about 0.5 mg to about 1.30 mg, from about 0.6 mg to about 1.25 mg,from about 0.7 mg to about 1.20 mg, from about 0.8 mg to about 1.15 mg,from about 0.9 mg to about 1.10 mg, or about 1.0 mg of talc. In certainembodiments, total amount of trihexyphenidyl hydrochloride present indrug layer-1 and drug layer-2 is from about 0.5% w/w to about 10% w/w,from about 1.0% w/w to about 9% w/w, from about 1.5% w/w to about 8.0%w/w, from about 2.0% w/w to about 7.0% w/w, from about 2.5% w/w to about6.5% w/w, from about 3.0% w/w to about 6.0% w/w, from about 3.5% w/w toabout 5.5% w/w, from about 4.0% w/w to about 5.0% w/w, or from about4.5% w/w to about 4.75% w/w, based on the total weight of thecomposition. In certain embodiments, total amount of hypromellose(METHOCEL® E5 Prem LV) present in drug layer-1 and drug layer-2 is fromabout 0.05% w/w to about 5.0% w/w, from about 0.10% w/w to about 4.5%w/w, from about 0.15% w/w to about 4.0% w/w, from about 1.0% w/w toabout 3.5% w/w, from about 1.25% w/w to about 3.4% w/w, from about 1.5%w/w to about 3.3% w/w, from about 1.75% w/w to about 3.2% w/w, fromabout 2.0% w/w to about 3.1% w/w, from about 2.25% w/w to about 3.0%w/w, from about 2.5% w/w to about 2.9% w/w, or from about 2.75% w/w toabout 2.8% w/w, based on the total weight of the dosage form. In certainembodiments, drug layer-1 and drug layer-2 comprise from about 0.01% w/wto about 0.3% w/w, from about 0.05% w/w to about 0.25% w/w, from about0.10% w/w to about 0.2% w/w, from about 0.11% w/w to about 0.19% w/w,from about 0.12% w/w to about 0.18% w/w, from about 0.13% w/w to about0.17% w/w, or from about 0.14% w/w to about 0.16% w/w of triethylcitrate, based on the total weight of the composition. In certainembodiments, drug layer-1 and drug layer-2 comprise from about 0.5% w/wto about 10% w/w, from about 1.0% w/w to about 9% w/w, from about 1.5%w/w to about 8.0% w/w, from about 2.0% w/w to about 7.0% w/w, from about2.5% w/w to about 6.5% w/w, from about 3.0% w/w to about 6.0% w/w, fromabout 3.5% w/w to about 5.5% w/w, from about 4.0% w/w to about 5.0% w/w,or from about 4.5% w/w to about 4.75% w/w of talc.

In certain embodiments, the functional coat comprises ethyl cellulose(or Eudragit S 100), hypromellose phthalate (HP 55), triethyl citrate,and talc. In certain embodiments, the functional coat comprises fromabout 1.0 mg to about 20 mg, from about 2.0 mg to about 19 mg, fromabout 3.0 mg to about 18 mg, from about 4.0 mg to about 17 mg, fromabout 5.0 mg to about 16 mg, from about 6.0 mg to about 15 mg, fromabout 7.0 mg to about 14 mg, from about 8.0 mg to about 13 mg, fromabout 9.0 mg to about 12, or from about 10 mg to about 11 mg of ethylcellulose. In certain embodiments, the functional coat comprises fromabout 0.1 mg to about 5.5 mg, from about 0.5 mg to about 5.0 mg, fromabout 1.0 mg to about 4.5 mg, from about 1.5 mg to about 4.0 mg, fromabout 2.0 mg to about 3.5 mg, or from about 2.5 mg to about 3.0 mg ofhypromellose phthalate (HP 55). In certain embodiments, the functionalcoat comprises from about 0.1 mg to about 3.0 mg, from about 0.5 mg toabout 2.5 mg, from about 1.0 mg to about 2.0 mg, or from about 1.25 mgto about 1.75 mg of triethyl citrate. In certain embodiments, thefunctional coat comprises from about 0.1 mg to about 5.5 mg, from about0.5 mg to about 5.0 mg, from about 1.0 mg to about 4.5 mg, from about1.5 mg to about 4.0 mg, from about 2.0 mg to about 3.5 mg, or from about2.5 mg to about 3.0 mg of talc. In certain embodiments, the functionalcoat comprises ethyl cellulose (or Eudragit S 100), hypromellosephthalate (or Hypromellose/Methocel E5 Prem LV), triethyl citrate, andtalc. In certain embodiments, the functional coat comprises from about8.0% w/w to about 25% w/w, from about 9.0% w/w to about 24% w/w, fromabout 10% w/w to about 23% w/w, from about 11% w/w to about 22% w/w,from about 12% w/w to about 21% w/w, from about 13% w/w to about 20%w/w, from about 14% w/w to about 19% w/w, from about 15% w/w to about18% w/w, or from about 16% w/w to about 17% w/w of ethyl cellulose (orEudragit S 100), based on the total weight of the composition. Incertain embodiments, the functional coat comprises from about 1% w/w toabout 4% w/w, from about 1.5% w/w to about 3.5% w/w, from about 2% w/wto about 3% w/w, from about 2.25% w/w to about 2.75% w/w, or about 2.5%w/w of hypromellose phthalate (or Hypromellose/Methocel E5 Prem LV),based on the total weight of the dosage form. In certain embodiments,the functional coat comprises from about 0.5% w/w to about 3% w/w, fromabout 1% w/w to about 2.5% w/w, from about 1.1% w/w to about 2.25% w/w,from about 1.2% w/w to about 2% w/w, from about 1.3% w/w to about 1.9%w/w, from about 1.4% w/w to about 1.8% w/w, from about 1.5% w/w to about1.7% w/w, or about 1.6% w/w of triethyl citrate, based on the totalweight of the dosage form. In certain embodiments, the functional coatcomprises from about 1.5% w/w to about 5% w/w, from about 2% w/w toabout 4.5% w/w, from about 2.5% w/w to about 4% w/w, from about 2.75%w/w to about 3.5% w/w, from about 3% w/w to about 3.4% w/w, from about3.1% w/w to about 3.3% w/w, or about 3.3% w/w of talc, based on thetotal weight of the dosage form.

In certain embodiments, the pellets of the present disclosure comprise acore, a seal coat, a drug layer, and a functional coat. In certainembodiments, the present disclosure provides for pellets that comprise acore comprising tartaric acid; a seal coat comprising hypromellose,triethyl citrate, and talc; a drug layer comprising trihexyphenidylhydrochloride, hypromellose, triethyl citrate and talc; a functionalcoat comprising ethyl cellulose, Eudragit S 100 (anionic copolymersbased on methacrylic acid and methyl methacrylate), hypromellosephthalate, hypromellose, triethyl citrate and talc.

In certain embodiments, the pellets of the present disclosure comprisefrom about 10.00 mg to about 250.00 mg of tartaric acid in the core;from about 1.50 mg to about 8.50 mg of hypromellose, from about 0.05 mgto about 0.45 mg of triethyl citrate and from about 0.40 mg to about2.00 mg of talc in the seal coat; from about 3.00 mg to about 7.00 mg oftrihexyphenidyl hydrochloride, from about 1.00 mg to about 5.00 mg ofhypromellose, from about 0.10 mg to about 0.20 mg of triethyl citrate,and from about 0.30 mg to about 1.00 mg of talc in the drug layer;optionally from about 5.00 mg to about 25.00 mg of ethyl cellulose,optionally from about 5.00 mg to about 15.00 mg of Eudragit S 100(anionic copolymers based on methacrylic acid and methyl methacrylate),optionally from about 1.00 mg to about 7.00 mg of hypromellosephthalate, optionally from about 1.50 mg to about 2.50 mg ofhypromellose, from about 0.50 mg to about 3.00 mg of triethyl citrate,and from about 1.00 to about 5.50 mg of talc in the functional coat. Incertain embodiments, the pellets of the present disclosure comprise fromabout 50% w/w to about 75% w/w of tartaric acid in the core; from about2.0% w/w to about 3.0% w/w of hypromellose, from about 0.10% w/w toabout 0.20% w/w of triethyl citrate and from about 0.50% w/w to about1.00% w/w of talc in the seal coat; from about 1.90% w/w to about 7.00%w/w of trihexyphenidyl hydrochloride, from about 1.00% w/w to about5.00% w/w of hypromellose, from about 0.10% w/w to about 0.25% w/w oftriethyl citrate, and from about 0.50% w/w to about 1.00% w/w of talc inthe drug layer; optionally from about 8.00% w/w to about 15.00% w/w ofethyl cellulose, optionally from about 10.00% w/w to about 15.00% w/w ofEudragit S 100 (anionic copolymers based on methacrylic acid and methylmethacrylate), optionally from about 2.0% w/w to about 3.5% w/w ofhypromellose phthalate, optionally from about 2.00% w/w to about 3.00%w/w of hypromellose, from about 1.00% w/w to about 2.00% w/w of triethylcitrate, and from about 2.00% w/w to about 4.00% w/w of talc in thefunctional coat, based on the total weight of the composition.

In a particular embodiment, a pellet of the present disclosure comprisesabout 70.98% w/w of tartaric acid in the core; about 2.73% w/w ofhypromellose, about 0.14% w/w of triethyl citrate, and about 0.68% w/wtalc in the seal coat; about 7.10% w/w of trihexyphenidyl hydrochloride,about 4.26% w/w of Hypromellose, about 0.21% w/w of triethyl citrate,and about 0.85% w/w of talc in the drug layer; about 8.04% w/w of ethylcellulose, about 2.00% w/w of hypromellose phthalate, about 1.01% w/w oftriethyl citrate, and about 2.00% w/w of talc in the functional coat,all amounts based on the total weight of the composition.

In another particular embodiment, a pellet of the present disclosurecomprises about 79.50% w/w of tartaric acid in the core; about 3.06% w/wof hypromellose, about 0.15% w/w of triethyl citrate, and about 0.76%w/w talc in the seal coat; about 1.99% w/w of trihexyphenidylhydrochloride, about 1.19% w/w of hypromellose, about 0.06% w/w oftriethyl citrate, and about 0.24% w/w of talc in the drug layer; about8.03% w/w of ethyl cellulose, about 2.01% w/w of hypromellose phthalate,about 1.00% w/w of triethyl citrate, and about 2.01% w/w of talc in thefunctional coat, all amounts based on the total weight of thecomposition.

In another particular embodiment, a pellet of the present disclosurecomprises about 65.30% w/w of tartaric acid in the core; about 2.51% w/wof hypromellose, about 0.13% w/w of triethyl citrate, and about 0.63%w/w talc in the seal coat; about 6.53% w/w of trihexyphenidylhydrochloride, about 3.92% w/w of hypromellose, about 0.20% w/w oftriethyl citrate, and about 0.78% w/w of talc in the drug layer; about13.07% w/w of ethyl cellulose, about 2.31% w/w of hypromellosephthalate, about 1.54% w/w of triethyl citrate, and about 3.08% w/w oftalc in the functional coat, all amounts based on the total weight ofthe composition.

In another particular embodiment, a pellet of the present disclosurecomprises about 60.47% w/w of tartaric acid in the core; about 2.51% w/wof hypromellose, about 0.13% w/w of triethyl citrate, and about 0.63%w/w talc in the seal coat; about 6.53% w/w of trihexyphenidylhydrochloride, about 3.92% w/w of hypromellose, about 0.20% w/w oftriethyl citrate, and about 0.78% w/w of talc in the drug layer; about13.07% w/w of ethyl cellulose, about 2.31% w/w of hypromellose, about1.54% w/w of triethyl citrate, and about 3.08% w/w of talc in thefunctional coat, all amounts based on the total weight of thecomposition.

In another particular embodiment, a pellet of the present disclosurecomprises about 60.47% w/w of tartaric acid in the core; about 2.32% w/wof hypromellose, about 0.12% w/w of triethyl citrate, and about 0.58%w/w talc in the seal coat; about 6.05% w/w of trihexyphenidylhydrochloride, about 3.63% w/w of hypromellose, about 0.18% w/w oftriethyl citrate, and about 0.73% w/w of talc in the drug layer; about16.95% w/w of ethyl cellulose, about 2.99% w/w of hypromellosephthalate, about 2.00% w/w of triethyl citrate, and about 3.99% w/w oftalc in the functional coat, all amounts based on the total weight ofthe composition.

In another particular embodiment, a pellet of the present disclosurecomprises about 65.31% w/w of tartaric acid in the core; about 2.51% w/wof hypromellose, about 0.13% w/w of triethyl citrate, and about 0.63%w/w talc in the seal coat; about 6.53% w/w of trihexyphenidylhydrochloride, about 3.92% w/w of hypromellose, about 0.20% w/w oftriethyl citrate, and about 0.78% w/w of talc in the drug layer; about12.3% w/w of Eudragit S 100 (anionic copolymers based on methacrylicacid and methyl methacrylate), about 3.08% w/w of hypromellosephthalate, about 1.54% w/w of triethyl citrate, and about 3.07% w/w oftalc in the functional coat, all amounts based on the total weight ofthe composition.

In another particular embodiment, a pellet of the present disclosurecomprises about 68.03% w/w of tartaric acid in the core; about 2.61% w/wof hypromellose, about 0.14% w/w of triethyl citrate, and about 0.65%w/w talc in the seal coat; about 6.80% w/w of trihexyphenidylhydrochloride, about 4.08% w/w of hypromellose, about 0.20% w/w oftriethyl citrate, and about 0.82% w/w of talc in the drug layer; about10.20% w/w of ethyl cellulose, about 2.56% w/w of hypromellosephthalate, about 1.29% w/w of triethyl citrate, and about 2.56% w/w oftalc in the functional coat, all amounts based on the total weight ofthe composition.

In another particular embodiment, a pellet of the present disclosurecomprises about 65.36% w/w of tartaric acid in the core; about 2.51% w/wof hypromellose, about 0.13% w/w of triethyl citrate, and about 0.63%w/w talc in the seal coat; about 6.54% w/w of trihexyphenidylhydrochloride, about 3.92% w/w of hypromellose, about 0.20% w/w oftriethyl citrate, and about 0.78% w/w of talc in the drug layer; about13.0% w/w of ethyl cellulose, about 2.30% w/w of hypromellose phthalate,about 1.53% w/w of triethyl citrate, and about 3.07% w/w of talc in thefunctional coat, all amounts based on the total weight of thecomposition.

In certain embodiments, the pellets of the present disclosure comprise acore, a seal coat-1, a drug layer-1, a functional coat, a seal coat-2, adrug layer-2, and an over coat. In certain embodiments, the pellets ofthe present disclosure comprise from about 25.00% w/w to about 75.00%w/w or tartaric acid in the core; from about 1.50% w/w to about 3.00%w/w of hypromellose, from about 0.05% w/w to about 0.20% w/w of triethylcitrate, and from about 0.40% w/w to about 0.75% w/w of talc in the sealcoat-1; from about 4.00% w/w to about 6.50% w/w of trihexyphenidylhydrochloride, from about 2.50% w/w to about 4.00% w/w of hypromellose,from about 0.10% w/w to about 0.25% w/w of triethyl citrate, and fromabout 0.50% w/w to about 1.00% w/w of talc in the drug layer-1; fromabout 5.00% w/w to about 20.00% w/w of ethyl cellulose, from about 1.00to about 3.50% w/w of hypromellose phthalate, from about 0.50% w/w toabout 2.50% w/w of triethyl citrate, and from about 1.25% w/w to about4.75% w/w of talc in the functional coat; optionally from about 2.75%w/w to about 4.50% w/w of hypromellose, optionally from about 0.70% w/wto about 1.10% w/w of talc, and optionally from about 0.05% w/w to about0.25% w/w of triethyl citrate in the seal coat-2; optionally from about0.50% w/w to about 1.50% w/w of trihexyphenidyl hydrochloride,optionally from about 0.50% w/w to about 1.00% w/w of succinic acid,optionally from about 1.00% w/w to about 2.50% w/w of tartaric acid,optionally from about 0.40% w/w to about 0.50% w/w of hypromellose,optionally from about 1.00% w/w to about 2.00% w/w of Copovidone,optionally from about 0.01% w/w to about 0.05% w/w talc, and optionallyabout 0.01% w/w of colloidal silicon dioxide in the drug layer-2;optionally from about 3.00% w/w to about 5.00% w/w of hypromellose,optionally from about 0.05% w/w to about 0.30% w/w of triethyl citrate,and from about 0.050% w/w to about 1.50% w/w of talc in the over coat,all amounts based on the total weight of the composition.

In a particular embodiment, a pellet of the present disclosure comprisesabout 58.65% w/w of tartaric acid in the core; about 2.25% w/w ofhypromellose, about 0.12% w/w of triethyl citrate, about 0.56% w/w oftalc in the seal coat-1; about 4.99% w/w of trihexyphenidylhydrochloride, about 2.99% w/w of hypromellose, about 0.18% w/w oftriethyl citrate, and about 0.65% w/w of talc in the drug layer-1; about11.50% w/w of ethyl cellulose, about 2.05% w/w of hypromellosephthalate, about 1.35% w/w of triethyl citrate, and about 2.70% w/w oftalc in the functional coat; about 3.45% w/w of hypromellose, about0.88% w/w of talc, and about 0.09% w/w of triethyl citrate in the sealcoat-2; about 0.88% w/w of trihexyphenidyl hydrochloride, about 0.88%w/w of succinic acid, about 0.53% w/w of hypromellose, about 0.02% w/wof triethyl citrate, about 0.53% w/w of talc, and about 0.01% w/w ofcolloidal silicon dioxide in the drug layer-2; about 3.73% w/w ofhypromellose, about 0.08% w/w of triethyl citrate, and 0.94% w/w of talcin the over coat, all amounts based on the total weight of thecomposition.

In another particular embodiment, a pellet of the present disclosurecomprises about 71.04% w/w of tartaric acid in the core; about 2.73% w/wof hypromellose, about 0.14% w/w of triethyl citrate, about 0.68% w/w oftalc in the seal coat-1; about 7.10% w/w of trihexyphenidylhydrochloride, about 4.26% w/w of hypromellose, about 0.21% w/w oftriethyl citrate, and about 0.85% w/w of talc in the drug layer-1; about8.50% w/w of ethyl cellulose, about 1.49% w/w of hypromellose phthalate,about 0.99% w/w of triethyl citrate, and about 1.99% w/w of talc in thefunctional coat, all amounts based on the total weight of thecomposition.

In another particular embodiment, a pellet of the present disclosurecomprises about 63.79% w/w of tartaric acid in the core; about 2.45% w/wof hypromellose, about 0.13% w/w of triethyl citrate, about 0.61% w/w oftalc in the seal coat-1; about 6.38% w/w of trihexyphenidylhydrochloride, about 3.83% w/w of hypromellose, about 0.19% w/w oftriethyl citrate, and about 0.77% w/w of talc in the drug layer-1; about14.30% w/w of ethyl cellulose, about 2.51% w/w of hypromellosephthalate, about 1.68% w/w of triethyl citrate, and about 3.36% w/w oftalc in the functional coat, all amounts based on the total weight ofthe composition.

In another particular embodiment, a pellet of the present disclosurecomprises about 57.4% w/w of tartaric acid in the core; about 2.21% w/wof hypromellose, about 0.11% w/w of triethyl citrate, about 0.55% w/w oftalc in the seal coat-1; about 5.75% w/w of trihexyphenidylhydrochloride, about 3.45% w/w of hypromellose, about 0.17% w/w oftriethyl citrate, and about 0.69% w/w of talc in the drug layer-1; about19.34% w/w of ethyl cellulose, about 3.40% w/w of hypromellosephthalate, about 2.28% w/w of triethyl citrate, and about 4.55% w/w oftalc in the functional coat, all amounts based on the total weight ofthe composition.

In another particular embodiment, a pellet of the present disclosurecomprises about 54.79% w/w of tartaric acid in the core; about 2.10% w/wof hypromellose, about 0.11% w/w of triethyl citrate, about 0.53% w/w oftalc in the seal coat-1; about 5.48% w/w of trihexyphenidylhydrochloride, about 3.29% w/w of hypromellose, about 0.16% w/w oftriethyl citrate, and about 0.66% w/w of talc in the drug layer-1; about21.50% w/w of ethyl cellulose, about 3.78% w/w of hypromellosephthalate, about 2.53% w/w of triethyl citrate, and about 5.06% w/w oftalc in the functional coat, all amounts based on the total weight ofthe composition.

In another particular embodiment, a pellet of the present disclosurecomprises about 57.30% w/w of tartaric acid in the core; about 2.20% w/wof hypromellose, about 0.11% w/w of triethyl citrate, about 0.55% w/w oftalc in the seal coat-1; about 4.87% w/w of trihexyphenidylhydrochloride, about 2.92% w/w of hypromellose, about 0.17% w/w oftriethyl citrate, and about 0.63% w/w of talc in the drug layer-1; about11.20% w/w of ethyl cellulose, about 2.01% w/w of hypromellosephthalate, about 1.32% w/w of triethyl citrate, and about 2.64% w/w oftalc in the functional coat; about 3.30% w/w of hypromellose, about0.83% w/w of talc, and about 0.17% w/w of triethyl citrate in the sealcoat-2; about 0.86% w/w of trihexyphenidyl hydrochloride, about 1.72%w/w of tartaric acid, about 1.24% w/w of Copovidone, and about 1.15% w/wof talc, in the drug layer-2; about 3.61% w/w of hypromellose, about0.18% w/w of triethyl citrate, and about 0.91% w/w of talc in the overcoat, all amounts based on the total weight of the composition.

In another particular embodiment, a pellet of the present disclosurecomprises about 52.85% w/w of tartaric acid in the core; about 2.43% w/wof hypromellose, about 0.13% w/w of triethyl citrate, about 0.60% w/w oftalc in the seal coat-1; about 5.39% w/w of trihexyphenidylhydrochloride, about 3.23% w/w of hypromellose, about 0.19% w/w oftriethyl citrate, and about 0.70% w/w of talc in the drug layer-1; about12.43% w/w of ethyl cellulose, about 2.22% w/w of hypromellosephthalate, about 1.46% w/w of triethyl citrate, and about 2.92% w/w oftalc in the functional coat; about 3.65% w/w of hypromellose, about0.91% w/w of talc, and about 0.19% w/w of triethyl citrate in the sealcoat-2; about 0.95% w/w of trihexyphenidyl hydrochloride, about 1.90%w/w of tartaric acid, about 1.37% w/w of Copovidone, and about 1.27% w/wof talc, in the drug layer-2; about 4.00% w/w of hypromellose, about0.20% w/w of triethyl citrate, and about 1.00% w/w of talc in the overcoat, all amounts based on the total weight of the composition.

In another particular embodiment, a pellet of the present disclosurecomprises about 47.29% w/w of tartaric acid in the core; about 2.72% w/wof hypromellose, about 0.14% w/w of triethyl citrate, about 0.68% w/w oftalc in the seal coat-1; about 6.03% w/w of trihexyphenidylhydrochloride, about 3.59% w/w of hypromellose, about 0.21% w/w oftriethyl citrate, and about 0.78% w/w of talc in the drug layer-1; about13.90% w/w of ethyl cellulose, about 2.46% w/w of hypromellosephthalate, about 1.63% w/w of triethyl citrate, and about 3.26% w/w oftalc in the functional coat; about 4.09% w/w of hypromellose, about1.02% w/w of talc, and about 0.21% w/w of triethyl citrate in the sealcoat-2; about 1.06% w/w of trihexyphenidyl hydrochloride, about 2.13%w/w of tartaric acid, about 1.53% w/w of Copovidone, and about 1.42% w/wof talc, in the drug layer-2; about 4.46% w/w of hypromellose, about0.23% w/w of triethyl citrate, and about 1.14% w/w of talc in the overcoat, all amounts based on the total weight of the composition.

In another particular embodiment, a pellet of the present disclosurecomprises about 58.53% w/w of tartaric acid in the core; about 2.25% w/wof hypromellose, about 0.12% w/w of triethyl citrate, about 0.56% w/w oftalc in the seal coat-1; about 5.41% w/w of trihexyphenidylhydrochloride, about 3.25% w/w of hypromellose, about 0.19% w/w oftriethyl citrate, and about 0.70% w/w of talc in the drug layer-1; about11.60% w/w of ethyl cellulose, about 2.07% w/w of hypromellosephthalate, about 1.36% w/w of triethyl citrate, and about 2.72% w/w oftalc in the functional coat; about 3.46% w/w of hypromellose, about0.88% w/w of talc, and about 0.09% w/w of triethyl citrate in the sealcoat-2; about 0.44% w/w of trihexyphenidyl hydrochloride, about 0.44%w/w of succinic acid, about 0.14% w/w of hypromellose, about 0.02% w/wof triethyl citrate, about 0.53% w/w of talc, and about 0.01% w/w ofcolloidal silicon dioxide in the drug layer-2; about 3.73% w/w ofhypromellose, about 0.08% w/w of triethyl citrate, and about 0.94% w/wof talc in the over coat, all amounts based on the total weight of thecomposition.

In another particular embodiment, a pellet of the present disclosurecomprises about 10.00 mg of tartaric acid in the core; about 0.384 mg ofhypromellose, about 0.02 mg of triethyl citrate, about 0.096 mg of talcin the seal coat-1; about 0.925 mg of trihexyphenidyl hydrochloride,about 0.555 mg of hypromellose, about 0.333 mg of triethyl citrate, andabout 0.120 mg of talc in the drug layer-1; about 1.982 mg of ethylcellulose, about 0.354 mg of hypromellose phthalate, about 0.233 mg oftriethyl citrate, and about 0.465 mg of talc in the functional coat;about 0.591 mg of hypromellose, about 0.151 mg of talc, and about 0.016mg of triethyl citrate in the seal coat-2; about 0.075 mg oftrihexyphenidyl hydrochloride, about 0.075 mg of succinic acid, about0.023 mg of hypromellose, about 0.004 mg of triethyl citrate, about 0.90mg of talc, and about 0.002 mg of colloidal silicon dioxide in the druglayer-2; about 0.636 mg of hypromellose, about 0.014 mg of triethylcitrate, and about 0.160 mg of talc in the over coat.

In another particular embodiment, a pellet of the present disclosurecomprises about 20.00 mg of tartaric acid in the core; about 0.77 mg ofhypromellose, about 0.04 mg of triethyl citrate, about 0.192 mg of talcin the seal coat-1; about 1.850 mg of trihexyphenidyl hydrochloride,about 1.110 mg of hypromellose, about 0.065 mg of triethyl citrate, andabout 0.239 mg of talc in the drug layer-1; about 3.963 mg of ethylcellulose, about 0.708 mg of hypromellose phthalate, about 0.465 mg oftriethyl citrate, and about 0.930 mg of talc in the functional coat;about 1.183 mg of hypromellose, about 0.302 mg of talc, and about 0.032mg of triethyl citrate in the seal coat-2; about 0.15 mg oftrihexyphenidyl hydrochloride, about 0.15 mg of succinic acid, about0.05 mg of hypromellose, about 0.01 mg of triethyl citrate, and about0.18 mg of talc in the drug layer-2; about 1.27 mg of hypromellose,about 0.03 mg of triethyl citrate, and about 0.32 mg of talc in the overcoat.

In another particular embodiment, a pellet of the present disclosurecomprises about 60.00 mg of tartaric acid in the core; about 2.304 mg ofhypromellose, about 0.120 mg of triethyl citrate, about 0.576 mg of talcin the seal coat-1; about 5.550 mg of trihexyphenidyl hydrochloride,about 3.330 mg of hypromellose, about 0.196 mg of triethyl citrate, andabout 0.718 mg of talc in the drug layer-1; about 11.890 mg of ethylcellulose, about 2.123 mg of hypromellose phthalate, about 1.395 mg oftriethyl citrate, and about 2.790 mg of talc in the functional coat;about 3.548 mg of hypromellose, about 0.905 mg of talc, and about 0.097mg of triethyl citrate in the seal coat-2; about 0.45 mg oftrihexyphenidyl hydrochloride, about 0.45 mg of succinic acid, about0.14 mg of hypromellose, about 0.02 mg of triethyl citrate, about 0.54mg of talc, and about 0.01 mg of colloidal silicon dioxide in the druglayer-2; about 3.82 mg of hypromellose, about 0.08 mg of triethylcitrate, and about 0.96 mg of talc in the over coat.

In another particular embodiment, a pellet of the present disclosurecomprises about 80.00 mg of tartaric acid in the core; about 3.072 mg ofhypromellose, about 0.16 mg of triethyl citrate, about 0.768 mg of talcin the seal coat-1; about 7.400 mg of trihexyphenidyl hydrochloride,about 4.440 mg of hypromellose, about 0.261 mg of triethyl citrate, andabout 0.958 mg of talc in the drug layer-1; about 15.853 mg of ethylcellulose, about 2.831 mg of hypromellose phthalate, about 1.860 mg oftriethyl citrate, and about 3.721 mg of talc in the functional coat;about 4.731 mg of hypromellose, about 1.207 mg of talc, and about 0.129mg of triethyl citrate in the seal coat-2; about 0.60 mg oftrihexyphenidyl hydrochloride, about 0.60 mg of succinic acid, about0.18 mg of hypromellose, about 0.03 mg of triethyl citrate, about 0.72mg of talc, and about 0.02 mg of colloidal silicon dioxide in the druglayer-2; about 5.09 mg of hypromellose, about 0.11 mg of triethylcitrate, and about 1.28 mg of talc in the over coat.

In another particular embodiment, a pellet of the present disclosurecomprises about 100.00 mg of tartaric acid in the core; about 3.84 mg ofhypromellose, about 0.20 mg of triethyl citrate, about 0.96 mg of talcin the seal coat-1; about 9.250 mg of trihexyphenidyl hydrochloride,about 5.550 mg of hypromellose, about 0.326 mg of triethyl citrate, andabout 1.197 mg of talc in the drug layer-1; about 19.816 mg of ethylcellulose, about 3.539 mg of hypromellose phthalate, about 2.325 mg oftriethyl citrate, and about 4.651 mg of talc in the functional coat;about 5.913 mg of hypromellose, about 1.508 mg of talc, and about 0.161mg of triethyl citrate in the seal coat-2; about 0.75 mg oftrihexyphenidyl hydrochloride, about 0.75 mg of succinic acid, about0.23 mg of hypromellose, about 0.04 mg of triethyl citrate, about 0.90mg of talc, and about 0.02 mg of colloidal silicon dioxide in the druglayer-2; about 6.36 mg of hypromellose, about 0.14 mg of triethylcitrate, and about 1.60 mg of talc in the over coat.

6.3. Compositions

In certain embodiments, the present disclosure provides compositionscomprising capsules containing a final blend comprising extended releasetrihexyphenidyl hydrochloride pellets, colloidal silicon dioxide, andtalc.

In certain embodiments, the final blend comprises from about 30 mg toabout 200 mg, from about 35 mg to about 175 mg, from about 40 mg toabout 150 mg, from about 45 mg to about 125 mg, or from about 50 mg toabout 100 mg of extended release THP pellets. In certain embodiments,the final blend comprises from about 0.01 mg to about 0.5 mg, from about0.05 mg to about 0.4 mg, from about 0.1 mg to about 0.3 mg, or fromabout 0.2 mg to about 0.25 mg of colloidal silicon dioxide. In certainembodiments, the final blend comprises from about 0.05 mg to about 0.6mg, from about 0.1 mg to about 0.5 mg, from about 0.15 mg to about 0.4mg, from about 0.2 mg to about 0.3 mg, or about 0.25 mg of talc.

In certain embodiments, the final blend comprises from about 30 mg toabout 200 mg, from about 35 mg to about 175 mg, from about 40 mg toabout 150 mg, from about 45 mg to about 125 mg, or from about 50 mg toabout 100 mg of extended release THP pellets; from about 0.01 mg toabout 0.5 mg, from about 0.05 mg to about 0.4 mg, from about 0.1 mg toabout 0.3 mg, or from about 0.2 mg to about 0.25 mg of colloidal silicondioxide; and from about 0.05 mg to about 0.6 mg, from about 0.1 mg toabout 0.5 mg, from about 0.15 mg to about 0.4 mg, from about 0.2 mg toabout 0.3 mg, or about 0.25 mg of talc. In certain embodiments, thefinal blend comprises from about 97% w/w to about 99.7%/w/w of extendedrelease THP pellets; from about 0.2% w/w to about 0.3% w/w of colloidalsilicon dioxide; and from about 0.2% w/w to about 0.3% w/w of talc.

In a particular embodiment, the final blend of the present disclosurecomprises about 102.01 mg of THP pellets, about 0.25 mg of colloidalsilicon dioxide, and about 0.25 mg of talc. In another particularembodiment, the final blend of the present disclosure comprises about17.002 mg of THP pellets, about 0.042 mg of colloidal silicon dioxide,and about 0.042 mg of talc. In another particular embodiment, the finalblend of the present disclosure comprises about 34.004 mg of THPpellets, about 0.08 mg of colloidal silicon dioxide, and about 0.08 mgof talc. In another particular embodiment, the final blend of thepresent disclosure comprises about 102.013 mg of THP pellets, about 0.25mg of colloidal silicon dioxide, and about 0.25 mg of talc. In anotherparticular embodiment, the final blend of the present disclosurecomprises about 136.018 mg of THP pellets, about 0.33 mg of colloidalsilicon dioxide, and about 0.33 mg of talc. In another particularembodiment, the final blend of the present disclosure comprises about170.022 mg of THP pellets, about 0.42 mg of colloidal silicon dioxide,and about 0.42 mg of talc. In another particular embodiment, the finalblend of the present disclosure comprises about 15.30 mg of THP pellets,about 0.10 mg of colloidal silicon dioxide, and about 0.10 mg of talc.In another particular embodiment, the final blend of the presentdisclosure comprises about 30.60 mg of THP pellets, about 0.20 mg ofcolloidal silicon dioxide, and about 0.20 mg of talc. In anotherparticular embodiment, the final blend of the present disclosurecomprises about 91.80 mg of THP pellets, about 0.60 mg of colloidalsilicon dioxide, and about 0.60 mg of talc. In another particularembodiment, the final blend of the present disclosure comprises about122.40 mg of THP pellets, about 0.80 mg of colloidal silicon dioxide,and about 080 mg of talc. In another particular embodiment, the finalblend of the present disclosure comprises about 153.0 mg of THP pellets,about 1.0 mg of colloidal silicon dioxide, and about 1.0 mg of talc.

6.4. Methods of Making

In certain embodiments, the present disclosure provides extended releasetrihexyphenidyl compositions providing and maintaining therapeuticallyeffective stable plasma concentrations of THP or a pharmaceuticallyacceptable salt thereof, without any initial burst release/dose dumping.In certain embodiments, the compositions of the disclosure provideextended release of THP or a pharmaceutically acceptable salt thereoffor at least about 10 hours, e.g., from about 16 hours to about 24hours, under physiologically relevant conditions.

The extended release trihexyphenidyl compositions of the disclosureinclude extended release pellets suitable for dosing in capsules,sachets, administration through feeding tubes, and as sprinkles on food,and liquids. In certain embodiments, the extended release pelletscomprise a core comprising an organic acid; a seal coat comprising awater-soluble, nonionic polymer over the core comprising organic acid; adrug layer comprising trihexyphenidyl hydrochloride over the seal coat;and a functional coat/rate controlling membrane, comprising a watersoluble polymer or an enteric polymer, a water-insoluble polymer, and aplasticizer, over the drug layer. In certain embodiments, the presenceof seal coat is optional. In certain embodiments, the core is sphericalor irregular in shape. In certain embodiments, the core is a pellet,bead/seed, or a granule comprising at least one organic acid. In certainembodiments, the core is a pellet, bead/seed, or a granule coated withat least one coating comprising at least one organic acid. In certainembodiments, the core is an organic acid or a mixture of organic acids.In a specific embodiment, organic acid granules are used as the core. Incertain embodiments, the core is an acid coated core comprising anonpareil seed coated with at least one coating comprising at least oneorganic acid, e.g., a cellet/sugar sphere coated with an organic acid.In certain embodiments, the core is a microcrystalline cellulose sphere,or a sugar sphere coated with at least one coating comprising at leastone organic acid. In certain embodiments, the organic acid coat over thenonpareil seed contains trihexyphenidyl or a pharmaceutically acceptablesalt thereof. In certain embodiments, the organic acid core is coatedwith a coat containing trihexyphenidyl or a pharmaceutically acceptablesalt thereof, and at least one additional organic acid. In certainembodiments, the additional organic acid in the coating can be same asthe organic acid present in the core. In certain embodiments, theadditional organic acid in the coating can be different from the organicacid present in the core.

In certain embodiments, the extended release pellets are made by coatingthe core comprising an organic acid with a seal coat (seal coat-1)comprising a nonionic water-soluble polymer, coating the seal-coatedcore with a drug layer comprising trihexyphenidyl hydrochloride and anonionic water-soluble polymer, and coating the drug-layered core with afunctional coat/membrane comprising a water-insoluble polymer, e.g.,ethyl cellulose and an enteric polymer, e.g., HP 55 (hypromellosephthalate). In certain embodiments, the functional coat is furthercoated with an immediate release drug layer (drug layer-2) containingtrihexyphenidyl hydrochloride for immediate release. In certainembodiments, there is a seal coat (seal coat-2) between the functionalcoat and drug layer-2. In certain embodiments, the presence of the sealcoat-2 and/or drug layer-2 is optional. In certain embodiments, the druglayer-2 contains trihexyphenidyl hydrochloride and an organic acid. Incertain embodiments, the organic acid in the core and the drug layer-2are different.

6.5. Methods of Use

In certain embodiments, the disclosure provides methods for treatingsymptoms of Parkinson's disease, cerebral palsy, dystonia, sialorrhea,dyskinesia, dystonia associated with cerebral palsy (dyskinetic cerebralpalsy), tremors, strokes, movement disorders, and any other disease ordisorder for which trihexyphenidyl is an appropriate treatment. Incertain embodiments, the disclosure provides methods for treatingparkinsonism, including primary or idiopathic Parkinson's disease,secondary symptomatic parkinsonism (postencephalitic, arteriosclerotic,infection-induced, tumor-induced, trauma-induced, and drug-induced), andinvoluntary movements due to side effects of certain psychiatric drugs.The methods comprise administering to a patient in need thereof, anextended release trihexyphenidyl composition of the disclosure suitablefor once- or twice-daily administration. In certain embodiments, thedisclosure provides methods for using extended release trihexyphenidylcompositions of the disclosure for use as an adjunct in the treatment ofall forms of parkinsonism and for the control of extrapyramidaldisorders caused by central nervous system drugs such asdibenzoxazepines, phenothiazines, thioxanthenes, and butyrophenones. Themethods comprise administering to a patient in need thereof, an extendedrelease trihexyphenidyl composition of the disclosure suitable for once-or twice-daily administration.

In certain embodiments, the disclosure provides methods for improvingpatient compliance by reducing symptoms, generally associated with highpeak serum concentrations (C_(max)) and high peak-to-trough fluctuationsprovided by immediate release trihexyphenidyl products. In certainembodiments, improving patient compliance comprises reducing symptoms ofdrowsiness, dizziness or blurred vision, dry mouth, stomach upset,vomiting, diarrhea, constipation, and difficulty in urinating andor/retention, confusion, agitation, and hallucinations, particularlyduring the night. The methods comprise administering the extendedrelease trihexyphenidyl compositions of the disclosure, wherein thecomposition provides a reduced C_(max), and reduced dose relatedpeak-to-trough fluctuations, e.g., C_(min):C_(max) ratio of greater thanor equal to 0.4 and FI of less than or equal to las compared to marketedIR trihexyphenidyl tablets. FIG. 8 compares pharmacokinetic data forArtane IR (5 mg BID), and Artane ER (10 mg QD) (see, Cheung et al.(1988), supra) with a 5 mg extended release Pellet 9 (Test T)(normalized to 10 mg). FIG. 8 demonstrates that Pellet 9 exhibitsreduced variability (e.g., C_(min):C_(max) ratio of greater than orequal to 0.4) in the plasma concentration of THP over an extended timeperiod compared to Artane ER (10 mg) and Artane IR (5 mg BID).

In certain embodiments, the disclosure provides methods for reducingside effects associated with currently marketed immediate releasetrihexyphenidyl compositions. In certain embodiments, the methodscomprise administering extended release trihexyphenidyl compositions ofthe disclosure that (1) reduce initial burst release/dose dumping and(2) maintain therapeutic plasma concentrations of the drug for extendedperiods of time. In certain embodiments, the therapeutic plasmaconcentrations depend on the severity of the patient's condition, and onthe strength of the THP composition administered to the patient. Incertain embodiments, the compositions of the disclosure contain fromabout 1% to about 20% w/w, based on the total weight of the composition,of trihexyphenidyl or a pharmaceutically acceptable salt thereof. Incertain embodiments, the compositions of the disclosure contain fromabout 1 mg to about 20 mg of trihexyphenidyl or a pharmaceuticallyacceptable salt thereof.

In certain embodiments, the disclosure provides methods for improvingpatient compliance by administering extended release trihexyphenidylcompositions of the disclosure, wherein the extended releasecompositions will allow for reduced frequency of administration of thecomposition, administration as sprinkle on solid food or liquids,administration via feeding tubes, and reduce side effects associatedwith high C_(max) levels and low C_(min):C_(max) ratios (i.e., <0.4 andFI of ≥1). In certain embodiments, the compositions of the disclosurereduce or avoid initial burst release (C_(max) above the therapeuticrange), while providing therapeutically effective amounts oftrihexyphenidyl hydrochloride for periods of at least about 10 hours,e.g., from about 16 hours to about 24 hours.

The following Examples illustrate the disclosure in a nonlimitingmanner. Unless indicated to the contrary, the numerical parameters setforth herein can vary depending upon the desired properties sought to beobtained by the present disclosure.

7. EXAMPLES Example 1: Preparation of Extended Release TrihexyphenidylHydrochloride Pellets (5 mg)

The present Example provides a summary of the preparation oftwenty-seven different extended release pellets as shown in Tables 1-4.Pellets 18-22 are dose proportional to Pellet 17 and Pellets 24-27 aredose proportional to Pellet 23.

TABLE 1 Pellet 1 Pellet 2 Pellet 3 Pellet 4 Pellet 5 Pellet 6 Pellet 7Pellet 8 % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w Composition(mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) Core Tartaric acid 70.98 79.5065.30 65.30 60.47 65.31 68.03 65.36 (50.0) (200.0) (50.0) (50.0) (50.0)(50.0) (50.0) (50.0) Seal Coat Hypromellose 2.73 3.06 2.51 2.51 2.322.51 2.61 2.51 (Methocel E5 (1.92) (7.70) (1.92) (1.92) (1.92) (1.92)(1.92) (1.92) Premium LV) Triethyl citrate 0.14 0.15 0.13 0.13 0.12 0.130.14 0.13 (0.1) (0.38) (0.1) (0.1) (0.1) (0.1) (0.1) (0.1) Talc 0.680.76 0.63 0.63 0.58 0.63 0.65 0.63 (0.47) (0.53) (0.44) (0.44) (0.40)(0.44) (0.46) (0.44) Coating Ethanol: Water (70:30) q.s. Solvent* DrugLayer Trihexyphenidyl 7.10 1.99 6.53 6.53 6.05 6.53 6.80 6.54hydrochloride (5.0) (5.0) (5.0) (5.0) (5.0) (5.0) (5.0) (5.0)Hypromellose 4.26 1.19 3.92 3.92 3.63 3.92 4.08 3.92 (Methocel E5 (3.0)(3.0) (3.0) (3.0) (3.0) (3.0) (3.0) (3.0) Premium LV) Triethyl citrate0.21 0.06 0.20 0.20 0.18 0.20 0.20 0.20 (0.15) (0.15) (0.15) (0.15)(0.15) (0.15) (0.15) (0.15) Talc 0.85 0.24 0.78 0.78 0.73 0.78 0.82 0.78(0.60) (0.60) (0.60) (0.60) (0.60) (0.60) (0.60) (0.60) Coating Ethanol:Water (80:20) q.s. Solvent* Functional Coat Ethyl cellulose 8.04 8.0313.07 13.07 16.95 NA 10.26 13.03 20 cps 95.66) (20.19) (10.01) (10.01)(14.02) (7.94) (9.97) Eudragit S 100 NA NA NA NA NA 12.30 NA NA (9.42)Hypromellose 2.00 2.01 2.31 NA 2.99 3.08 2.56 2.30 phthalate (HP (1.41)(5.05) (1.77) (2.47) (2.36) (1.88) (1.76) 55) Hypromellose NA NA NA 2.31NA NA NA NA (Methocel E5 (1.77) Premium LV) Triethyl citrate 1.01 1.001.54 1.54 2.00 1.54 1.29 1.53 (0.71) (2.52) (1.18) (1.18) (1.65) (1.18)(0.95) 1.17) Talc 2.00 2.01 3.08 3.08 3.99 3.07 2.56 3.07 (1.41) (5.05)(2.36) (2.36) (3.30) 2.35) (1.88) (2.35) Coating Ethanol: Water (70:30)q.s. Solvent* Total Weight 100.00 100.00 100.00 100.00 100.00 100.00100.00 100.00 (70.44) (251.56) (76.57) (76.57) (82.69) (76.56) (73.50)(73.56) *Removed during process

TABLE 2 Pellet 9 Pellet 10 Pellet 11 Pellet 12 Pellet 13 Pellet 14Pellet 15 Pellet 16 % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/wComposition (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) Core Tartaric acid58.65 71.04 63.79 57.49 54.79 57.35 52.8 47.29 (50.0) (50.0) (50.0)(50.0) (50.0) (50.0) (50.0) (50.0) Seal Coat-1 Hypromellose 2.25 2.732.45 2.21 2.10 2.20 2.43 2.72 (Methocel E5 (1.92) (1.92) (1.92) (1.92)(1.92) (1.92) (2.30) (2.88) Premium LV) Triethyl citrate 0.12 0.14 0.130.11 0.11 0.11 0.13 0.14 (0.10) (0.10) (0.10) (0.10) (0.10) (0.10)(0.12) (0.15) Talc 0.56 0.68 0.61 0.55 0.53 0.55 0.60 0.68 (0.48) (0.48)(0.48) (0.48) (0.48) (0.48) (0.57) (0.72) Coating Ethanol: Water (70:30)q.s. Solvent* Drug Layer-1 Trihexyphenidyl 4.99 7.10 6.38 5.75 5.48 4.875.39 6.03 hydrochloride (4.25) (5.0) (5.0) (5.0) (5.0) (4.25) (5.1)(6.37) Hypromellose 2.99 4.26 3.83 3.45 3.29 2.92 3.23 3.59 (Methocel E5(2.55) (3.0) (3.0) (3.0) (3.0) (2.55) (3.06) (3.8) Premium LV) Triethylcitrate 0.18 0.21 0.19 0.17 0.16 0.17 0.19 0.21 (0.15) (0.15) (0.15)(0.15) (0.15) (0.15) (0.18) (0.225) Talc 0.65 0.85 0.77 0.69 0.66 0.630.70 0.78 (0.55) (0.60) (0.60) (0.60) (0.60) (0.55) (0.66) (0.825)Coating Ethanol: Water (80:20) q.s. Solvent* Functional Coat Ethylcellulose 11.50 8.50 14.30 19.34 21.50 11.24 12.43 13.90 20 cps (9.80)(5.98) (11.21) 16.82) (19.62) (9.8) (11.6) (14.7) Hypromellose 2.05 1.492.51 3.40 3.78 2.01 2.22 2.46 phthalate (HP (1.75) (1.05) (1.97) (2.96)(3.45) (1.75) (2.1) (2.6) 55) Triethyl citrate 1.35 0.99 1.68 2.28 2.531.32 1.46 1.63 (1.15) (0.70) (1.32) (1.98) (2.31) 1.15) (1.38) (1.72)Talc 2.70 1.99 3.36 4.55 5.06 2.64 2.92 3.26 (2.30) (1.40) 2.63) (3.96)(4.62) (2.30) (2.76) (3.45) Coating Ethanol: Water (70:30) q.s. Solvent*Seal Coat-2 Hypromellose 3.45 NA NA NA NA 3.30 3.65 4.09 (Methocel E5(2.94) (2.88) (3.45) (4.32) Premium LV) Talc 0.88 NA NA NA NA 0.83 0.911.02 (0.75) (0.72) (0.86) (1.08) Triethyl citrate 0.09 NA NA NA NA 0.170.19 0.21 (0.08) (0.15) (0.18) (0.225) Coating Ethanol: Water (70:30)q.s. Solvent* Drug Layer-2 Trihexyphenidyl 0.88 NA NA NA NA 0.86 0.951.06 hydrochloride (0.75) (0.75) (0.9) (1.12) Succinic acid 0.88 NA NANA NA NA NA NA (0.75) Tartaric acid NA NA NA NA NA 1.72 1.90 2.13 (1.50)(1.80) (2.25) Hypromellose 0.53 NA NA NA NA NA NA NA (Methocel E5 (0.45)Premium LV) Copovidone NA NA NA NA NA 1.24 1.37 1.53 (1.08) (1.30)(1.62) Triethyl citrate 0.02 NA NA NA NA NA NA NA (0.02) Talc 0.53 NA NANA NA 1.15 1.27 1.42 (0.45) (1.0) (1.2) (1.5) Colloidal silicon 0.01 NANA NA NA NA NA NA dioxide (0.01) Coating Ethanol: Water (80:20) q.s.Solvent* Over Coat Hypromellose 3.73 NA NA NA NA 3.61 4.00 4.46(Methocel E5 (3.18) (3.15) 3.78) (4.72) Premium LV) Triethyl citrate0.08 NA NA NA NA 0.18 0.20 0.23 (0.07) (0.16) (0.19) (0.24) Talc 0.94 NANA NA NA 0.91 1.00 1.14 (0.80) (0.79) (0.95) (1.2) Coating Ethanol:Water (70:30) q.s. Solvent* Total Weight 100.00 100.00 100.00 100.00100.00 100.00 100.00 100.00 (84.53) (70.38) (78.38) (86.97) (91.25)(87.18) (94.6) (105.71) *Removed during process

TABLE 3 Pellet 17 Pellet 18 Pellet 19 Pellet 20 Pellet 21 Pellet 22Composition % w/w (mg) (mg) (mg) (mg) (mg) (mg) Core Tartaric acid 58.53(50) 10.0 20.0 60.0 80.0 100.0 Seal Coat-1 Hypromellose 2.25 (1.92)0.384 0.77 2.304 3.072 3.84 (Methocel E5 Premium LV) Triethyl citrate0.12 (0.10) 0.02 0.04 0.120 0.16 0.2 Talc 0.56 (0.48) 0.096 0.192 0.5760.768 0.96 Coating Ethanol: Water (70:30) q.s. Solvent* Drug Layer-1Trihexyphenidyl 5.41 (4.625) 0.925 1.850 5.550 7.400 9.250 hydrochlorideHypromellose 3.25 (2.775) 0.555 1.110 3.330 4.440 5.550 (Methocel E5Premium LV) Triethyl citrate 0.19 (0.163) 0.333 0.065 0.196 0.261 0.326Talc 0.70 (0.599) 0.120 0.239 0.718 0.958 1.197 Coating Ethanol: Water(80:20) q.s. Solvent* Functional Coat Ethyl cellulose 11.60 (9.91) 1.9823.963 11.890 15.853 19.816 20 cps Hypromellose 2.07 (1.77) 0.354 0.7082.123 2.831 3.539 phthalate (HP 55) Triethyl citrate 1.36 (1.16) 0.2330.465 1.395 1.860 2.325 Talc 2.72 (2.33) 0.465 0.930 2.790 3.721 4.651Coating Ethanol: Water (70:30) q.s. Solvent* Seal Coat-2 Hypromellose3.46 (2.96) 0.591 1.183 3.548 4.731 5.913 (Methocel E5 Premium LV) Talc0.88 (0.75) 0.151 0.302 0.905 1.207 1.508 Triethyl citrate 0.09 (0.08)0.016 0.032 0.097 0.129 0.161 Coating Ethanol: Water (70:30) q.s.Solvent* Drug layer-2 Trihexyphenidyl 0.44 (0.375) 0.075 0.15 0.45 0.600.75 hydrochloride Succinic acid 0.44 (0.375) 0.075 0.15 0.45 0.60 0.75Hypromellose 0.14 (0.113) 0.023 0.05 0.14 0.18 0.23 (Methocel E5 PremiumLV) Triethyl citrate 0.02 (0.02) 0.004 0.01 0.02 0.03 0.04 Talc 0.53(0.450) 0.090 0.18 0.54 0.72 0.90 Colloidal silicon 0.01 (0.010) 0.0020.00 0.01 0.02 0.02 dioxide Coating Ethanol: Water (80:20) q.s. Solvent*Over Coat (5% of IR layered pellets) Hypromellose 3.73 (3.18) 0.636 1.273.82 5.09 6.36 (Methocel E5 Premium LV) Triethyl citrate 0.08 (0.07)0.014 0.03 0.08 0.11 0.14 Talc 0.94 (0.80) 0.160 0.32 0.96 1.28 1.60Total weight 99.52 (85.01) 17.004 34.009 102.012 135.969 170.026 CoatingEthanol: Water (70:30) q.s. Solvent* Final Blend THP over 99.52 (102.01)17.002 34.004 102.013 136.018 170.022 coated pellets Colloidal silicon0.24 (0.25) 0.042 0.08 0.25 0.33 0.42 dioxide Talc 0.24 (0.25) 0.0420.08 0.25 0.33 0.42 Total fill 100.00 (102.51) 17.086 34.171 102.513136.684 170.855 weight in capsule *Removed during process

TABLE 4 Pellet Pellet Pellet Pellet Pellet Composition 23 (mg) 24 (mg)25 (mg) 26 (mg) 27 (mg) Tartaric acid 10.0 20.0 60.0 80.0 100.0 SealCoat Hypromellose 0.384 0.768 2.304 3.072 3.840 (Methocel E5 Premium LV)Triethyl citrate 0.020 0.040 0.120 0.160 0.200 Talc 0.096 0.192 0.5760.768 0.960 Coating Ethanol:Water (70:30) Solvent* Drug Layer Trihexy-1.00 2.00 6.00 8.00 10.00 phenidyl hydrochloride Hypromellose 0.600 1.203.60 4.80 6.00 (Methocel E5 Premium LV Triethyl citrate 0.03 0.06 0.180.24 0.30 Talc 0.12 0.24 0.72 0.96 1.20 Coating Ethanol:Water (80:20)Solvent* Functional Coat Ethyl cellulose 2.00 4.00 12.00 16.00 20.00(ETHOCEL 20 Premium) Hypromellose 0.350 0.70 2.10 2.80 3.50 phthalate(HP 55) Triethyl citrate 0.23 0.46 1.38 1.84 2.30 Talc 0.47 0.94 2.803.76 4.70 Coating Ethanol:Water (70:30) Solvent* Total Weight 15.3030.60 91.80 122.40 153.00 Final Blend THP HCl 15.30 30.60 91.80 122.40153.00 Functional coated pellets Colloidal 0.10 0.20 0.60 0.80 1.00silicon dioxide (CAB-O-SIL) Talc 0.10 0.20 0.60 0.80 1.00 Total Weight15.50 31.00 93.00 124.00 155.00 *Removed during process

The pellets were made according to the following manufacturingprocedure.

Manufacturing Procedure:

A. Seal Coat-1:

A-1: Hypromellose was added to a mixture of ethanol (200 proof) andwater (70:30 w/w ratio) in a stainless-steel container and mixed until aclear solution was obtained.

A-2: To the clear solution from step #A-1, triethyl citrate was addedand mixed for not less than 15 minutes to obtain a clear solution.

A-3: To the clear solution from step #A-2, talc was added and mixeduntil a uniform dispersion was obtained.

A-4: Cores comprising tartaric acid were taken in a Wurster chamber andseal coated with the dispersion from step #A-3 until target coatingweight gain was achieved.

B. Drug Layer-1:

B-1: Trihexyphenidyl hydrochloride was added to a mixture of ethanol(200 proof) and water (80:20 w/w ratio) in a stainless-steel containerand mixed until a clear solution was obtained.

B-2: To the clear solution from step #B-1, hypromellose was added withconstant stirring and mixed until a clear solution was obtained.

B-3: To the clear solution from step #B-2, triethyl citrate was addedand mixed for not less than 15 minutes to obtain a clear solution.

B-4: To the clear solution from step #B-3, talc was added and mixeduntil a uniform dispersion was obtained.

B-5: Seal coated pellets from procedure A were taken in a Wursterchamber and coated with the dispersion from step #B-4.

C. Functional Coat:

C-1: Ethyl cellulose or Eudragit S100 was added to ethanol (200 proof)in a stainless-steel container and mixed until a clear solution wasobtained.

C-2: To the clear solution from step #C-1, water was added and mixed fornot less than 30 minutes to obtain a clear solution.

C-3: To the clear solution from step #C-2, hypromellose phthalate orhypromellose was added and mixed until a clear or light hazy solutionwas obtained.

C-4: To the solution from step #C-3, triethyl citrate was added andmixed for not less than 15 minutes to obtain a clear solution.

C-5: To the clear solution from step #C-4, talc was added and mixed toobtain a uniform dispersion.

C-6: Drug layered pellets from procedure B were taken in a Wursterchamber and coated with the dispersion from step #C-5 until targetcoating weight gain was achieved.

C-7: Functional coated pellets from step #C-6 were dried between about25° C. and about 30° C.

D. Seal Coat-2:

D-1: Hypromellose was added to a mixture of ethanol 200 proof and water(70:30 w/w ratio) in a stainless-steel container and mixed until a clearsolution was obtained.

D-2: To the solution from step #D-1, triethyl citrate was added andmixed for not less than 15 minutes to obtain a clear solution.

D-3: To the solution from step #D-2, talc was added and mixed until auniform dispersion was obtained.

D-4: Functional coated pellets (pellets 9, and 14-22) from Step C weretaken in a Wurster chamber and seal coated with the dispersion from step#D-3 until target coating weight gain was achieved.

E. Drug Layer-2:

E-1: Trihexyphenidyl hydrochloride and succinic acid were added to amixture of ethanol (200 proof) and water (80:20 w/w ratio) in astainless-steel container and mixed to form a clear solution.

E-2: To the solution from step #E-1, hypromellose was added withconstant stirring and mixed until a clear solution was obtained.

E-3: To the solution from step #E-2, triethyl citrate was added andmixed for not less than 15 minutes to obtain a clear solution.

E-4: To the clear solution from step #E-3, colloidal silicon dioxide andtalc were added and mixed until a uniform dispersion was obtained.

E-5: Pellets with seal coat-2 (Pellets 9 and 14-22) from Step D weretaken in a Wurster chamber and coated with the dispersion from step#E-4.

F. Over Coat:

F-1: Hypromellose was added to a mixture of ethanol 200 proof and water(70:30 w/w ratio) in a stainless-steel container and mixed until a clearsolution was obtained.

F-2: To the solution from step #F-1, triethyl citrate was added andmixed for not less than 15 minutes to obtain a clear solution.

F-3: To the clear solution from step #F-2, talc was added and mixeduntil a uniform dispersion was obtained.

F-4: Pellets with drug layer-2 (Pellets 9 and 14-22) from Step E weretaken in a Wurster chamber and coated with the dispersion from step #F-3until target coating weight gain was achieved.

G. Trihexyphenidyl Hydrochloride Capsules:

G-1: A final blend of functional coated pellets (from Step C or Step F)along with talc and/or colloidal silicon dioxide was prepared using aV-Blender and then filled into hard gelatin capsules based on therequired fill weight.

Example 2: Additional Compositions

Pellets 28-33 are made according to the manufacturing proceduredescribed in Example 1. Pellets 28 and 29 contain drug:acid weight ratioof 1:50 and 1:100, respectively. Both pellets include a functionalcoating weight gain of about 25% w/w, based on the total weight of thepellet without functional coat; and a water-insoluble polymer:poreformer weight ratio of 85:15. Pellet 30 and 31 include water-insolublepolymer:pore former weight ratio of 50:50 and 98:2, respectively. Bothpellets contain a drug:acid weight ratio of 1:10, and a functionalcoating weight gain of about 25% w/w, based on the total weight of thepellet without functional coat. Pellet 32 and 33 contain a functionalcoating weight gain of about 5% w/w and about 40% w/w, respectively,based on the total weight of the pellet without the functional coat.Both pellets contain a drug:acid weight ratio of 1:10, and awater-insoluble polymer:pore former weight ratio of 85:15.

TABLE 5 Pellet 28 Pellet 29 Pellet 30 Pellet 31 Pellet 32 Pellet 33Composition (mg) (mg) (mg) (mg) (mg) (mg) Tartaric acid 50 mg 100 mg 10mg 10 mg 10 mg 10 mg Seal Coat Hypromellose 1.92 3.840 0.3840 0.38400.3840 0.3840 (Methocel E5 Premium LV) Triethyl citrate 0.1 0.2 0.020.02 0.02 0.02 Talc 0.48 0.96 0.096 0.096 0.096 0.096 Drug LayerTrihexyphenidyl 1.00 1.00 1.00 1.00 1.00 1.00 hydrochloride Hypromellose0.6 0.6 0.6 0.6 0.6 0.6 (Methocel E5 Premium LV Triethyl citrate 0.030.03 0.03 0.03 0.03 0.03 Talc 0.12 0.12 0.12 0.12 0.12 0.12 Total Weight54.25 106.8 12.25 12.25 12.25 12.25 Functional Coat Ethyl cellulose 8.8717.46 1.175 2.30 0.40 4.00 (ETHOCEL 20 Premium) Hypromellose 1.56 3.081.175 0.05 0.07 0.71 phthalate (HP 55) Triethyl citrate 1.04 2.05 0.230.23 0.05 0.47 Talc 2.08 4.11 0.47 0.47 0.09 0.94 Total Weight 67.80133.5 15.3 15.3 12.86 18.37 Final Blend THP HCl 67.82 133.5 15.3 15.3012.86 18.37 Functional coated pellets Talc 0.44 0.87 0.1 0.1 0.08 0.12Colloidal silicon dioxide (CAB- 0.44 0.87 0.1 0.1 0.08 0.12 O-SIL) TotalWeight 68.70 135.24 15.5 15.5 13.03 18.6 *Removed during process

Example 3: Comparison of Dissolution Profiles of TrihexyphenidylHydrochloride (API (Control)) and Trihexyphenidyl HydrochlorideDrug-Layered Pellets, without Functional Coat

Dissolution tests were performed for trihexyphenidyl hydrochloride (API(control)) and for trihexyphenidyl hydrochloride drug-layered pellets(Pellets 1A-1D). Pellet 1A is drug layered Pellet 1 without functionalcoat and containing about 25% drug layer weight gain, based on the totalweight of the seal coated pellet without the drug layer. Pellet 1B isdrug layered Pellet 1 without functional coat and containing about 50%drug layer weight gain, based on the total weight of the seal coatedpellet without the drug layer. Pellet 1C is drug layered Pellet 1without functional coat and containing about 75% drug layer weight gain,based on the total weight of the seal coated pellet without the druglayer. Pellet 1D is drug layered Pellet 1 without functional coat andcontaining about 100% drug layer weight gain, based on the total weightof the seal coated pellet without the drug layer. The dissolutions wereperformed in an incubator orbital shaker, in 20 ml of pH 6.8 phosphatebuffer at 37° C. Drug release was measured using high performance liquidchromatography (HPLC) for API (control) and tartaric acid pellets 1A-1Dat 5, 10, 20, 30, and 60 minutes.

FIG. 1 shows the effects of tartaric acid on solubility oftrihexyphenidyl hydrochloride at pH 6.8. FIG. 1 demonstrates thattartaric acid provides an acidic microenvironmental pH for improvingdissolution of trihexyphenidyl hydrochloride at pH 6.8. API (control)without any tartaric acid, released about 0.66 mg/ml of trihexyphenidylhydrochloride at 5 minutes, whereas the drug-layered pellets with 25%drug layer weight gain released about 1.9 mg/ml of trihexyphenidylhydrochloride at 5 minutes, and the drug-layered pellets with 50, 75,and 100% drug layer weight gain released about 1.7 mg/ml oftrihexyphenidyl hydrochloride at 5 minutes. FIG. 1 demonstrates thatpresence of tartaric acid-containing cores increased the amount of THPreleased at a pH of about 5 or above. The figure further demonstratesthat increasing the amount of drug layer reduced the amount of THPreleased at a pH of about 5 or above.

TABLE 6 Pellet 1A Pellet 1B Pellet 1C Pellet 1D Composition (mg) (mg)(mg) (mg) Tartaric acid 50.00 50.00 50.00 50.00 Seal Coat Hypromellose1.92 1.92 1.92 1.92 (Methocel E5 Premium LV) Triethyl citrate 0.10 0.100.10 0.10 Talc 0.60 0.60 0.60 0.60 Total weight 52.62 52.62 52.62 52.62Drug Layer Trihexyphenidyl 8.30 16.60 24.90 33.20 hydrochlorideHypromellose 5.00 10.00 15.00 20.00 (Methocel E5 Premium LV) Triethylcitrate 0.25 0.50 0.75 1.00 Talc 1.00 2.00 3.00 4.00 Total drug layer14.55 29.10 43.65 58.20 weight (mg)

Example 4: Effect of Functional Coat on Release Rate of TrihexyphenidylHydrochloride

Two-stage dissolution tests for trihexyphenidyl hydrochloride capsulescontaining THP pellets of the disclosure without any functional coat,and capsules containing THP pellets of the disclosure with 13% wt gainof the functional coat, were performed using USP Apparatus I at 100 RPMand 37° C., in 900 ml of 0.01 N HCl for 1 hour followed by dissolutionin 900 ml of pH 6.8 phosphate buffer for 24 hours, to simulatephysiological conditions. Samples were collected at regular intervals oftime, and drug release was measured using HPLC. The results are shown inFIG. 2. As illustrated by FIG. 2, the functional coat helped to reduceand/or prevent the initial burst release of trihexyphenidylhydrochloride and provided a more even release of the THP HCl— Pellet 1without a functional coat provided faster dissolution/higher dissolutionrate compared to the Pellet 1 with a functional coat.

Example 5: Effect of Trihexyphenidyl Hydrochloride and Tartaric AcidWeight Ratio on the Release Rate of Trihexyphenidyl Hydrochloride

Two-stage dissolution tests for THP HCl capsules containing theformulation of Pellet 1, and THP HCl capsules containing the formulationof Pellet 2, were performed using USP Apparatus I at 100 RPM and 37° C.,in 900 ml of 0.01 N HCl for 1 hour followed by dissolution in 900 ml ofpH 6.8 phosphate buffer for 24 hours, to simulate physiologicalconditions. Pellets 1 and 2 contained about 13% coating wt gain offunctional coat. Pellet 1 contained a tartaric acid:THP HCl weight ratioof about 10:1, and Pellet 2 contained a tartaric acid:THP HCl weightratio of about 40:1. Samples were collected at regular intervals of timeand drug release was measured using HPLC. FIG. 3 demonstrates thatPellet 2 formulation, with a tartaric acid to THP HCl weight ratio of40:1, provided a much higher dissolution rate compared to Pellet 1formulation, with a tartaric acid to THP HCl weight ratio of 10:1,indicating that the amount of acid in the core was directly proportionalto the dissolution rate of the drug at pH 6.8.

Example 6: Comparison of Trihexyphenidyl Hydrochloride Release Profilefrom Pellet 1 Formulation and Marketed IR Trihexyphenidyl HydrochlorideTablets, 5 Mg, in pH 6.8 Phosphate Buffer

Dissolution tests for THP HCl capsules containing Pellet 1 formulationand marketed IR THP HCl tablets, 5 mg, were performed using USPApparatus I at 100 RPM and 37° C., in 900 ml of pH 6.8 phosphate bufferfor 24 hours. Samples were collected at regular intervals of time anddrug release was measured using HPLC. FIG. 4 compares dissolutionprofiles of Pellet 1 formulation and marketed IR THP HCl tablets (5 mg).FIG. 4 demonstrates that the marketed IR THP HCl tablet provided fasterdissolution of THP HCl compared to Pellet 1 formulation. FIG. 4demonstrates that the marketed THP HCl tablet provided initial burstrelease of THP, whereas the Pellet 1 formulation provided controlledrelease, no initial burst release, of THP. The slow release oftrihexyphenidyl from the Pellet 1 formulation was attributed to thepresence of controlled release membrane comprising ethyl cellulose andhypromellose phthalate (HP 55). Further, tartaric acid provided anacidic microenvironmental pH for improving solubility and recovery (bythe end of 24 hours) of THP HCl, even at pH 6.8.

Example 7: Effect of Ethyl Cellulose and Hypromellose Phthalate WeightRatio on Trihexyphenidyl Hydrochloride Dissolution Profile

Two-stage dissolution tests for capsules containing Pellet 7 [ethylcellulose:hypromellose phthalate (80:20)] formulation, and for capsulescontaining Pellet 8 [ethyl cellulose:hypromellose phthalate (85:15)]formulation were performed using USP Apparatus I at 100 RPM and 37° C.,in 900 ml of 0.01 N HCl for one hour followed by dissolution in 900 mlof pH 6.8 phosphate buffer for 24 hours, to simulate physiologicalconditions. Pellet 7 contained functional coat containing ethylcellulose:hypromellose phthalate weight ratio of about 80:20 at about20% functional coating weight gain, based on the total weight of thepellet without the functional coat, Pellet 8 contained a functional coatcontaining ethyl cellulose:hypromellose phthalate weight ratio of about85:15 at about 25% functional coating weight gain, based on the totalweight of the pellet without functional coat. Samples were collected atregular intervals of time and drug release was measured using HPLC. FIG.5 compares the dissolution profiles of capsules containing Pellets 7 and8 respectively. FIG. 5 demonstrates that Pellet 8 containing ethylcellulose:hypromellose phthalate weight ratio of 85:15 at 25% functionalcoating weight gain provided a reduced drug release rate and morecontrolled release compared to pellet 7 containing ethylcellulose:hypromellose phthalate weight ratio of about 80:20 at 20%functional coating weight gain. FIG. 5 demonstrates that release of THPHCl is reduced with increase in functional coating weight gain.

Example 8: Effect of Functional Coat Weight Gain on Release Rate ofTrihexyphenidyl Hydrochloride

Two-stage dissolution tests for trihexyphenidyl hydrochloride capsulescontaining pellets 5, 11, 12, and 13 with about 25%, about 20%, about30%, and about 35% coating weight gain of functional coat, respectively,based on the total weight of the corresponding pellets without thefunctional coat, were performed using USP Apparatus I at 100 RPM and 37°C., in 900 ml of pH 1.2 medium for 1 hour followed by dissolution in 900ml of pH 6.8 phosphate buffer for 24 hours, to simulate physiologicalconditions. Samples were collected at regular intervals of time, anddrug release was measured using HPLC. The ratio of nonionicwater-insoluble polymer:pore former in all pellets was about 85:15. Theresults of the Experiment are illustrated in FIG. 6. FIG. 6 demonstratesthat the drug release rate increased with decreasing functional coatweight gain. Pellets with 20% wt gain of the functional coat providedmaximum release rate and recovery of THP HCl, and pellets with 35% wtgain of the functional coat provided lowest release rate and recovery ofTHP HCl.

Example 9: Comparison of Trihexyphenidyl Hydrochloride Release Profilefrom Pellets with and without an Immediate Release Drug Layer

Two-stage dissolution tests for trihexyphenidyl hydrochloride capsulescontaining Pellets 5, 15, and 16 were performed using USP Apparatus I at100 RPM and 37° C., in 900 ml of pH 1.2 HCl for one hour followed bydissolution in 900 ml of pH 6.8 phosphate buffer for 24 hours, tosimulate physiological conditions. Samples were collected at regularintervals of time, and drug release was measured using HPLC. Pellet 5contained 5 mg of trihexyphenidyl hydrochloride in drug layer-1 (ERlayer) and contained no drug layer-2 (IR layer); Pellet 15 contained 5.1mg of trihexyphenidyl hydrochloride in drug layer-1 and 0.9 mg oftrihexyphenidyl hydrochloride in drug layer-2; and Pellet 16 contained6.37 mg of trihexyphenidyl hydrochloride in drug layer-1 and 1.125 mg oftrihexyphenidyl hydrochloride in drug layer-2. FIG. 7 demonstrates thatPellet 5 (without drug layer-2) provided a lag time to therapeutic drugconcentration of about 2 hours, and Pellets 15 and 16 (containing druglayer-2) provided a lag time to therapeutic drug concentration of about30 minutes.

Example 10: Comparison of Dissolution Profile of Pellets Containing aCombination of pH Independent Water-Insoluble Polymer and an EntericPolymer; a Combination of a pH Independent Water-Insoluble and a pHIndependent Water-Soluble Polymer; and Pellets Containing a Combinationof Two Enteric Polymers

Two-stage dissolution tests for trihexyphenidyl hydrochloride capsulescontaining Pellet 3 [ethyl cellulose:hypromellose phthalate (85:15)]formulation, trihexyphenidyl hydrochloride capsules containing Pellet 4[ethyl cellulose:hypromellose (85:15)] formulation, and trihexyphenidylhydrochloride capsules containing Pellet 6 [Eudragit® S 100:Hypromellosephthalate (85:15)] formulation were performed using USP Apparatus I at100 RPM and 37° C., in 900 ml of pH 1.2 medium for one hour followed bydissolution in 900 ml of pH 6.8 phosphate buffer for 24 hours, tosimulate physiological conditions. Samples were collected at regularintervals of time and drug release was measured using HPLC. FIG. 9compares the two-stage dissolution profiles of Pellets 3, 4, and 6. FIG.9 demonstrates that the type of water-insoluble polymer and the type ofpore former in the functional coat plays a critical role in controllingthe release rate of trihexyphenidyl hydrochloride. FIG. 9 demonstratesthat Pellet 3 containing ethocel and hypromellose phthalate (HP 55)provided more controlled release of the drug compared to Pellet 4containing ethocel and hypromellose (Methocel E5 Prem LV), and Pellet 6containing Eudragit S100 and hypromellose phthalate (HP 55) in thefunctional coat.

Example 11: Oral Bioavailability of THP HCl from Extended ReleaseCompositions of the Disclosure

A single dose pharmacokinetic (PK) study was conducted in healthyvolunteers under fed conditions to evaluate and compare the PKperformance of extended release THP HCl capsules containing Pellet 8 (5mg) of the present disclosure with a marketed immediate release THP HClreference product R (5 mg). An open label, balanced, randomized,two-treatment, two-period, two-sequence, single oral dose, two-waycrossover bioequivalence study of reference product R (IR THP HCltablets, 5 mg) with capsules containing Pellet 8 was conducted in 14normal healthy adult human subjects under high fat-high calorieconditions after 10 hour overnight fasting.

Pharmacokinetic results from the study are summarized below.

TABLE 7 Pharmacokinetic Geometric Mean Parameters Capsules with Pellet 8Reference Product R Cmax (ng/ml) 7.808 31.879 Cmin (ng/ml) 6.162 6.50Cav (ng/ml) 5.17 12.56 FI 0.326 1.99 AUC_(0-t) (hr · ng/ml) 171.521318.511 AUC_(0-∞) (hr · ng/ml) 281.227 454.522 Tmax (h)* 6.00 2.00*median (min-max)

The data from Table 7/FIG. 10 demonstrates that the extended release THPcapsules containing Pellet 8 provided a Cmin:Cmax ratio of >0.4 and FIof <1 and provided therapeutic concentrations of THP HCl over at leastabout 16 hours, and the immediate release reference product R provided aCmin:Cmax ratio of <0.4 and FI>1. C_(max) of the extended releasecapsules containing Pellet 8 was about 25% of the immediate releasereference product R.

Example 12: Oral Bioavailability of THP HCl from Extended ReleaseCompositions of the Disclosure

A single dose pharmacokinetic (PK) study was conducted in healthyvolunteers under fed conditions to evaluate and compare the PKperformance of extended release THP HCl composition (6 mg) of thepresent disclosure, administered once-a-day, with marketed immediaterelease THP HCl product (2 mg)/reference product R, administered 3times-a-day. An open label, balanced, non-randomized, two-treatment,two-period, single-sequence, crossover oral bioavailability study ofreference product R, administered three time-a-day (IR THP HCl tablets,2 mg×3), with extended release capsules containing Pellet 17, at pelletweight adjusted to 6 mg strength and a fill weight of about 102.5 mg,administered once-a-day, was conducted in 20 normal healthy adult humansubjects under high fat-high calorie conditions after 10 hour overnightfasting.

Pharmacokinetic results from the study are summarized below.

TABLE 8 Pharmacokinetic Geometric Mean Parameters Capsules with Pellet17 Reference Product (R) Cmax (ng/ml) 12.050 13.190 AUC_(0-t) (hr ·ng/ml) 229.787 252.89 AUC_(0-∞) (hr · ng/ml) 294.863 345.228 Tmax (h)*4.00 17.75 *median (min-max)

PK data from Table 8/FIG. 11 demonstrates that the extended release THPcapsules (6 mg), administered once-a-day, provided substantially reducedC_(max)-to-C_(min) fluctuations (e.g., C_(min):C_(max) ratio of ≥0.4),while providing therapeutic concentrations of THP HCl over about 24hours, compared to marketed immediate release 2 mg THP tablets/referenceproduct R, administered three-times-a-day (C_(min):C_(max) ratio of<0.4). The PK data further suggests that under fed conditions, the testproduct (extended release THP HCl composition (6 mg) of the presentdisclosure, administered once-a-day) and the reference productR(immediate release THP HCl product (2 mg), administered 3 times-a-day),provided similar bioavailability (Test AUC_(0-∞)/Reference AUC_(0-∞) is˜92%).

Example 13: Oral Bioavailability of THP HCl from Extended ReleaseCompositions of the Disclosure Under Fed and Fasted Conditions

A single dose pharmacokinetic (PK) study was conducted in healthyvolunteers, under fed and fasting conditions, to evaluate and comparethe PK performance, under fed and fasted conditions, of extended releaseTHP HCl composition (6 mg) of the present disclosure, with marketedimmediate release THP HCl product/reference product R (2 mg). An openlabel, balanced, randomized, two-treatment, two-period, two groups,single oral dose, two-sequence, two-way crossover oral bioavailabilitystudy of extended release capsules containing Pellet 25 (6 mg THP) andof reference product R, was conducted in normal healthy adult humansubjects under fed and fasting conditions.

Pharmacokinetic results from the study are summarized below.

TABLE 9 Pharmacokinetic Geometric Mean Parameters Test product ReferenceProduct (R) Pharmacokinetic Fed Fasting Fed Fasting Parameters ConditionCondition Condition Condition Cmax (ng/ml) 13.8 9.4 12.3 17.9 AUC_(0-∞)(hr · ng/ml) 431.8 335.6 214.4 166

PK data from Table 9, suggest that the test product and referenceproduct R have similar food effect on bioavailability (FastingAUC_(0-∞)/Fed AUC_(0-∞) is ˜78%).

Table 10/FIG. 15 provides PK data for extended release capsulescontaining Pellet 25 (6 mg THP HCl, QD dosing) and of reference productR (QD dosing simulated for TID, 2 mg×3), in normal healthy adult humansubjects under fed conditions.

TABLE 10 FED CONDITION C_(max) C_(min) C_(min)/C_(max) Cav FI AUC₀₋₂₄Reference (R)- 16.57 5.08 0.306 10.13 1.13 254.4 N = 18 Capsules 13.086.98 0.533  6.74 0.90 179.8 with Pellet 25 (T) N = 18

Table 11/FIG. 16 provides PK data for extended release capsulescontaining Pellet 25 (6 mg THP HCl) and of reference product R (QDdosing simulated for TID, 2 mg×3), in normal healthy adult humansubjects under fasting conditions.

TABLE 11 FASTING CONDITION C_(max) C_(min) C_(min)/C_(max) Cav FIAUC₀₋₂₄ Reference (R)- 20.12 2.83 0.14 9.16 1.89 216.6 N = 18 Capsuleswith 9.4 4.78  0.508 5.41 0.81 134.2 Pellet 25 (T) N = 18

The data from 10/FIG. 15 and Table 11/FIG. 16 demonstrates that theextended release THP capsules (6 mg), administered once-a-day, providedsubstantially reduced C_(max)-to-C_(min) fluctuations (e.g.,C_(min):C_(max) ratio of ≥0.4 and FI of ≤1), while providing therapeuticconcentrations of THP HCl over about 24 hours, compared to marketedimmediate release 2 mg THP tablets/reference product R, administeredthree-times-a-day.

The present disclosure is well adapted to attain the ends and advantagesmentioned, as well as those that are inherent therein. The particularembodiments disclosed above are illustrative only, as the presentdisclosure can be modified and practiced in different but equivalentmanners apparent to those skilled in the art having the benefit of theteachings herein. Furthermore, no limitations are intended to thedetails of construction or design herein shown, other than as describedin the claims below. It is therefore evident that the particularillustrative embodiments disclosed above can be altered or modified, andall such variations, including but not limited to substitution ofdifferent trihexyphenidyl salts, are considered within the scope andspirit of the present disclosure. Various publications, patents, andpatent application are cited herein, the contents of which are herebyincorporated-by-reference herein in their entireties.

The invention claimed is:
 1. A pharmaceutical pellet compositioncomprising: a) a core comprising at least one organic acid; b) a druglayer covering at least a portion of the core; and c) a functional coatcovering at least a portion of the drug layer, wherein the drug layercomprises trihexyphenidyl or a pharmaceutically acceptable salt thereof,and a nonionic water-soluble polymer, wherein the functional coatcomprises a nonionic water-insoluble polymer, and a pore former, whereinthe water-insoluble polymer and the pore former are present in a weightratio of from about 60:40 to about 98:2, and wherein the compositionprovides extended release with a C_(min):C_(max) ratio of ≥0.4.
 2. Thecomposition of claim 1, wherein the composition provides and maintainsat least a minimum therapeutic plasma concentration of thetrihexyphenidyl or the pharmaceutically acceptable salt thereof duringthe extended release.
 3. The composition of claim 1, wherein the minimumtherapeutic plasma concentration is a minimum concentration of thetrihexyphenidyl or the pharmaceutically acceptable salt thereof that canprovide a therapeutically useful response in a subject.
 4. Thecomposition of claim 1, wherein the composition provides a FluctuationIndex of ≤1.
 5. The composition of claim 1, wherein the core is apellet, bead, seed, or a granule comprising at least one organic acid.6. The composition of claim 1, wherein the core is a pellet, bead, seed,or a granule coated with at least one coating comprising at least oneorganic acid.
 7. The composition of claim 1, wherein the core is anorganic acid or a mixture of organic acids.
 8. The composition of claim1, wherein the first drug layer comprises trihexyphenidyl hydrochloride.9. The composition of claim 1, wherein the composition is suitable foronce-a-day administration.
 10. The composition of claim 1, wherein theorganic acid is selected from the group consisting of tartaric acid,citric acid, fumaric acid, succinic acid, malic acid, and mixturesthereof.
 11. The composition of claim 1, wherein the nonionicwater-soluble polymer in the drug layer is selected from the groupconsisting of hydroxypropyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, polyethylene glycol, polyvinylalcohol, poloxamer, polyvinyl pyrrolidone-vinyl acetate copolymer, andmixtures thereof.
 12. The composition of claim 1, wherein the nonionicwater-insoluble polymer in the functional coat is selected from thegroup consisting of ethyl cellulose, cellulose acetate, cellulosediacetate, cellulose triacetate, cellulose propionate, a polyvinylacetate dispersion, and mixtures thereof.
 13. The composition of claim1, wherein the pore former is an enteric polymer selected from the groupconsisting of cellulose acetate phthalate, cellulose acetate succinate,methylcellulose phthalate, hydroxyethyl cellulose phthalate, polyvinylacetate phthalate, polyvinyl butyrate acetate, vinyl acetate-maleicanhydride copolymer, methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetylphthalate, and mixtures thereof.
 14. The composition of claim 1, whereinthe pore former is a nonionic, pH-independent water-soluble polymerselected from the group consisting of methyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose,polyethylene glycol, polyvinyl alcohol, poloxamer, polyvinylpyrrolidone-vinyl acetate copolyme, and mixtures thereof.
 15. Thecomposition of claim 1, wherein the drug layer further comprises atleast one organic acid selected from the group consisting of tartaricacid, citric acid, fumaric acid, succinic acid, malic acid, and mixturesthereof.
 16. A pharmaceutical composition comprising: a) a corecomprising at least one organic acid; b) a drug layer covering at leasta portion of the core; and c) a functional coat covering at least aportion of the drug layer, wherein the drug layer comprisestrihexyphenidyl or a pharmaceutically acceptable salt thereof, and anonionic water-soluble polymer, wherein the functional coat comprises anonionic water-insoluble polymer, and a pore former, wherein thewater-insoluble polymer and the pore former are present in a weightratio of from about 60:40 to about 98:2, and wherein the compositionprovides a Fluctuation Index of ≤1.
 17. The composition of claim 16,wherein the core is an organic acid or a mixture of organic acids. 18.The composition of claim 16, wherein the core comprises at least oneorganic acid.
 19. The composition of claim 16, wherein the core is apellet, bead, seed, or a granule coated with at least one coatingcomprising at least one organic acid.
 20. A method for making apharmaceutical pellet composition comprising trihexyphenidyl or apharmaceutically acceptable salt thereof, the method comprising: a)coating a core comprising at least one organic acid, with a drug layercomprising trihexyphenidyl or a pharmaceutically acceptable saltthereof, and a nonionic water-soluble polymer, to obtain a drug layeredcore, b) coating the drug layered core with a functional coat comprisinga nonionic water-insoluble polymer, and a pore former; wherein thewater-insoluble polymer and the pore former are present in a weightratio of from about 60:40 to about 98:2, and wherein the compositionprovides extended release with a C_(min):C_(max) ratio of ≥0.4.
 21. Themethod of claim 20, wherein the core is an organic acid or a mixture oforganic acids; comprises at least one organic acid; or is a pellet,bead, seed, or a granule coated with at least one coating comprising atleast one organic acid.
 22. A method for treating symptoms ofParkinson's disease, the method comprising orally administering to asubject in need thereof, a pharmaceutical pellet composition comprising:a) a core comprising at least one organic acid; b a drug layer coveringat least a portion of the core; and c) a functional coat covering atleast a portion of the drug layer, wherein the drug layer comprisestrihexyphenidyl or a pharmaceutically acceptable salt thereof, and anonionic water-soluble polymer, wherein the functional coat comprises anonionic water-insoluble polymer, and a pore former, wherein thewater-insoluble polymer and the pore former are present in a weightratio of from about 60:40 to about 98:2, and wherein the compositionprovides a C_(min):C_(max) ratio of ≥0.4.